A

Mode of action of the aliphatic nitrogen mustards Theoretically, this type of alkylation resembles a SN2 process since the ratecontrolling step is the bimolecular reaction between the cyclic aziridinium ion and the nucleophile which involves simultaneous bond formation and breakage. The preceding step, involving iminium ion formation, is a fast unimolecular process. In practice it is difficult to draw sharp distinctions between the contributions of SN1- and SN2-type mechanisms. The aromatic...

Gj NkT log iiin

Using the log10 scale, NkT 1.418 kcal mol-1 at blood temperature (37 C). Thus for two conformers differing in energy by l kcal mol-1, log10 n2 n1 0.7 (where conformer 2 is the more favourable) giving a conformer population ratio n2 n1 of 5 1 at this temperature. (From Davies (1987), by permission) The utility of Equation 3.10 is shown by a simple example in Figure 3.9 where the bioactive conformer with the basic side chain perpendicular to the aromatic ring...

AspA rgVal TyrlleHi sPto PheHi sLeu AspArg VaiTyr fleHis Pro

During the initial stages of development of ACE inhibitors, little was known concerning its structure and characteristics other than that it was a zinc-dependent enzyme. In the early work a model of the active site of ACE was tentatively constructed, based on information from the well known structure of carboxypeptidase A, where a zinc moiety at the active site forms a complex with the scissile amide bond of the peptide substrate and a positively charged residue binds to the negatively charged...

B117 R CHF 8118 R CHFj

Fluoride ion to give the enimine (8.120) (see Equations 8.40 and 8.41 ). The electrophilic centres developed in the conjugated systems by the normal or abnormal electron flow react with a nucleophile at the active site of the enzyme. More recent work with other pyridoxal phosphate-dependend enzymes has suggested an alternative mechanism, which is llustrated in Equation 8.42 for the fluoromethyl derivatives. Here the enimines dissociate from the pyridoxal phosphate to give an enamine which then...

Cc c g

Figure 12.1 Insertion of foreign DNA into a bacterial plasmid. Figure 12.1 Insertion of foreign DNA into a bacterial plasmid. Resistant cells can then be isolated, propagated and tested to determine whether the required protein is being synthesized by the cells. This is achieved by exposing dishes on which cultures are growing to cellulose nitrate filters. If the cultures are producing the required protein this protein will be adsorbed onto the surface of the filter. Subsequent exposure of the...

Cephalexin

Thus, the British Pharmacopoeia (1993) defines ampicillin as (6R)-6-(a-D-phenylgrycylamino) penicillanic acid (4.35) and cephalexin as acid (4.36). The side chain chiral centre being denoted by the D L system and only in the case of ampicillin is the stereochemistry of the ring system indicated and then for only one of the three chiral centres. Within the literature the two possible diastereoisomers arising from the introduction of the side chain of such...

Ceranapril

Membrane metalloendopeptidase inhibitors Membrane metalloendopeptidase (MEP, also known as enkephalinase and neutral endopeptidase) is involved in the deactivation of the enkephalin pentapeptides and other peptides and hormones including atrial natriuretic peptide (ANP), Substance P, cholecystokinin, bradykinin and chemotactic peptide. MEP cleaves the enkephalin pentapeptides (Tyr-Gly-Gly-Phe-Leu Met) at the Gly3-Phe4 bond and much of the earlier work has focused on inhibition of enkephalin...

Ch H

Renal excretion is the net result of glomerular filtration, active secretion and passive and active reabsorption (see Chapter 1). Since glomerular filtration is a passive process differences between enantiomers would not be expected, stereoselective renal clearance may be observed as a result of active secretion, however active reabsorption and renal metabolism may also be significant. Apparent stereoselectivity in renal clearance may also arise as a consequence of stereoselectivity in protein...

Ch3

R)-11-Hydroxy-10-methylaporphine (4.92) is a highly selective 5-HT1A agonist, whereas its S-antipode (4.92) is an antagonist at the same receptor. Similarly, (S)-apomorphine (4.93) acts as an antagonist at dopaminergic receptors (D1 and D2) whereas the R-enantiomer is an agonist. In the case of 11-hydroxyaporphine the Renantiomer activates dopamine receptors and the S-enantiomer is an antagonist. A similar though more complex situation arises with...

Chch2mhchch3i

Table 4.5 Pharmacological activity of the stereoisomers of labetalol. Table 4.5 Pharmacological activity of the stereoisomers of labetalol. show increased toxicity is at present unknown. Labetalol dilevalol represents an interesting example indicating that removal of unrequired stereoisomers from a mixture may not be a trivial matter. The 4-hydroxycoumarin anticoagulants act by competitive inhibition of the vitamin K dependent step in clotting factor synthesis. Warfarin (4.77), and the related...

CljCCHjOpchohjona 712

The antiepileptic activities of methylphenobarbitone (Prominal ) (7.13), primidone (Mysoline ) (7.14) and methsuximide (7.15) have also been shown to be related to the plasma levels of active metabolites. The active metabolites are obtained on demethylation of methylphenobarbitone and oxidation of primidone. Methsuximide is also demethylated and at steady state the metabolite of this compound has been shown to be present at 700-fold greater concentrations than the parent drug. The non-steroidal...

Cn

Some examples of the use of single isomers versus racemic mixtures of relatively old compounds in the clinic are also known, e.g. D-penicillamine and L-dopa (4.64). The use of both these compounds as pure enantiomers, rather than their racemates, resulted in a decrease in toxicity. The initial use of racemic dopa for the treatment of Parkinson's disease resulted in nausea, vomiting, anorexia, involuntary movements and granulocytopenia. The use of L-dopa resulted in halving the required dose, a...

Cnptoprii

Development of other inhibitors has also been based on the concept of biproduct inhibition. Optimization of orientations of the C-terminus carboxyl and amide carbonyl for binding to the enzyme by incorporating some features of succiny-L-proline into an Ala-Pro 'backbone' led to the development of thiol-free inhibitors such as enalaprilat (8.49). This had a better side effect profile than captopril but was not active when given orally. The ethyl ester enalapril is well absorbed and is...

Cyclophosphamide

Molecules exist in either left or right handed spirals in the same way that a corkscrew, or spiral staircase, may be either left (4.17) or right (4.18) handed. Thus, chirality may arise as a result of helicity in a structure. While the above example has little significance in medicinal chemistry it is important to appreciate that a number of biologically important macromolecules exist as helical structures. For example the a-helix of proteins, composed of L-a-amino acids, is right handed and...

Design Of Enzyme Inhibitors As Drugs

ANJANA PATEL, H.JOHN SMITH and JORG STURZEBECHER 8.1.2 Types of inhibitors 264 8.2 GENERAL ASPECTS OF INHIBITOR DESIGN 271 8.2.1 Target enzyme and inhibitor selection 271 8.2.2 Specificity and toxicity 273 8.3 RATIONAL APPROACH TO THE DESIGN OF ENZYME INHIBITORS 275 8.4 DEVELOPMENT OF A SUCCESSFUL DRUG FOR 8.6 EXAMPLES OF ENZYME INHIBITORS AS 8.6.1 Protease inhibitors 283 8.6.1.1 Serine proteases 284 8.6.1.3 Aspartate proteases 309 8.6.2 Acetylcholinesterase inhibtors 317 8.6.3 Aromatase...

Dyflos

The organophosphorus compounds have a long duration of action in the body after a single dose of the drug and enzyme activity only returns after synthesis of fresh enzyme. Due to dangers of overdosage, as well as handling, they are little used except for treatment of glaucoma where the other less toxic cabamate drugs have not proved satisfactory in a particular therapy.

Figure 114 Effect of lactamases on susceptible cephalosporins

The situation with susceptible cephalosporins is more complex. Opening of the p-lactam ring again occurs (11.26) and this is accompanied by expulsion of the group at R2 (except in cephalexin, where R2 is H). The molecule finally breaks up into fragments (see Figure 11.4). Extensive studies have shown that several types of p-lactamases exist among Gram-negative bacteria. These have been classified into several different groups on the basis of their substrate...

Figure 62 Effects of tight binding on inhibition

Compounds in Figure 6.2 in sequence they are very approximately 10.3, approx. 9.3 and 8.1. For tight-binding corrected pIC50 (-log IC50) values subtract 0.3 from pKi. The data in Figure 6.2 show that the imidazole (6.20), X Y CH, may be the most potent inhibitor yet described. Modelling studies indicated that additional lipophilic substituents fusions at C4 and or C5 could produce yet further substantial improvements but these ideas were not pursued because ICI 207658 had been identified as a...

Further Reading

Aldridge, W.N. (1989) Cholinesterase and esterase inhibitors and reactivation of organophosphorus inhibited esterases. In Design of Enzyme Inhibitors as Drugs, edited by M.Sandler and H.J.Smith, Vol. 1, pp. 294-313. Oxford Oxford University Press. (a) Bode, W., Huber, R., Rydel, T.J. and Tulinsky, A. (1992) X-Ray crystal structures of human a-thrombin and of the human thrombin-hirudin complex. (b) Powers, J.C. and Kam, C.-M. (1992) Synthetic substrates and inhibitors of thrombin. (c) Stone,...

GABAtransaminase H succinic

Y-Acetylenic GABA (8.114) is a time-dependent inhibitor of GABA-T but also inhibits other pyridoxal phosphate-dependent enzymes, y-vinyl GABA (vigabatrin, 8.115) acts in a similar manner through its (S)-enantiomer but has a more specific action. Vigabatrin has shown promise as a drug for the treatment of epilepsy. Studies on drug-resistant epileptic patients have indicated that additional therapy with vigabatrin reduces seizures by over 50 in more than half the population studied without...

H

Histamine derivatives resulted in 2-(3-bromophenyl)histamine (10.49) and its trifluoromethyl analogue (10.50). These compounds have 112 and 128 relative activity, respectively. Compounds (10.49) and (10.50) make the H1-receptor mediated biological functions in experimental characterization much more precise than former tools. Most people have allergic and inflammation reactions on their mind when thinking of histamine. Compounds preventing this response to histamine are the first so called...

H H

(1131) 1,3-diajacTOjiychlprampheiii(rol Another way in which bacteria show resistance to antibiotics is by an intrinsic type of resistance associated, in Gram-negative bacteria especially, with the cell wall. The cell envelope of such organims is considerably more chemically complex than the envelopes of Gram-positive bacteria, which consist predominanatly of peptidoglycan and teichoic acids (Figure 11.1a). Figure 11.1b presents a simplified version of the cell envelope of Gram-negative cells....

HCHsCH o

Although these molecules possess chloroethyl fragments, their activity is not associated with aziridinium ion formation as in the mustards, since the corresponding nitrogen atom is part of a urea structure and so the electron pair on the nitrogen is not available to participate in a cyclisation reaction. Although the mechanism of action has not been firmly established, it is thought that the alkylation of nucleic acids proceeds via generation of a chloroethyl carbonium ion. The alkyl isocyanate...

I4123

RCQ- represents palmitate or oleate residues and ArCHiCH X O- a 2-arylpropionyl residue ) benoxaprofen undergo significant inversion in man, whereas the reaction either does not occur or is relatively minor for indoprofen, flurbiprofen, ketoprofen and carprofen. In addition to chiral inversion a number of these agents show stereoselectivity in plasma protein binding (e.g. fraction unbound ibuprofen enantiomers S> R) and in other routes of metabolism, e.g. glucuronidation and oxidation. In...

IfiN HjO Hf Qc Oco N F

There is an exception to the ranking of F2 and O2 which can be understood in terms of the hybrid p character of the donor lone pairs where the mixing of n-type lone pairs with the c-type lone pair increases the charge transfer. On the other hand in the non-hydrogen Table 3.1 Natural bond orbital charge transfer analysis of some H-bonded and non H-bonded complexes (calculations at HF 6-31G* level) involving HF, H2O, and NH3. Energies in kcal mol-1. Table 3.1 Natural bond orbital charge transfer...

Info

Phenylbutazone (Butozolidine ) (7.23) is converted by the body into the two hydroxylated forms, oxyphenbutazone (7.24) and (7.25). The drug is used in therapy under hospital supervision, mainly as an antiinflammatory agent, and this activity resides in form (7.24). However, another use of the drug is as a uricosuric agent, in the treatment of gout, and this action is attributable to the form (7.25). The observation that substitution in the side-chain of phenylbutazone results in enhanced...

J CHjCHOHCHj

(paracetamol) (7.28), as well as to an inactive metabolite, the glucuronide of 2-hydroxyl phenacetin (7.29), in small amounts. Paracetamol has replaced phenacetin in therapy, since it is usually free from toxic effects associated with phenacetin, e.g. methaemoglobin formation. However, extensive hepatic necrosis may occur when overdoses are ingested since the normal biotransformation pathway (conjugation with glutathione) is then saturated and a highly reactive metabolite is formed which binds...

J9 tli orphan

A sulphonic acid instead of a carboxy group e.g. m-aminobenzenesulphonic derivatives show a high degree of inhibitory potency and selectivity for MEP. Hydrogen bond doner group. This binds with the terminal amide (peptide) linkage. Evidence that the amide group of the peptide bond between AA1 and AA2 is hydrogen bonded to the active site of the enzyme comes from the observation that N-methylation of the peptide link in the dipeptides Phe-Gly, Phe-Ala or Phe-Leu, leads to 100-fold reduction in...

Jg3g5

Hydroxyethylene isostere and a hydroxyethylamine isostere, is also orally active. The sulphonamido moiety, in the novel (R)-hydroxy ethyl sulphonamides isostere (8.86), has also been used to replace the P1'P2' amide linkage of the inhibitor (8.87, Ki 1 nM). Symmetrical inhibitors (8.88, IC50 0.2 nM 8.89, Ki 0.8 pM) capitalize on the unique symmetry of the homodimeric enzyme. Unlike transition-state analogues, the stereochemistry of the two hydroxyl groups is not significant. Modifications to...

Jog lC i1 kirc t jtjE Jtjna frirE faaE kxitaE h

Figure 5.6 Distribution consisting of two clusters. Interrelationships between parameters must be eliminated before a correlation can be considered acceptable, for two reasons. Firstly, the use of highly correlated parameters makes mechanistic interpretation of the QSAR difficult secondly high intercorrelation can render the statistical analysis unstable. Before an expression of the form of Equation 5.42 can be considered valid, linear regressions should be carried out between each pair of...

K 1 MfL

A second constant K2 describes the stability of the 2 1 complex ML2. A cumulative constant, p K1.K2, is used to describe the overall reactions Mn' + L Mir and ML1 11 + V - ML, When considering whether the modus operandi of a new or existing pharmaceutical may involve metal ion complexing it is helpful to be able to predict which metal ion-drug interactions may occur and how strong they will be. Such predictions can be made using the hard and soft acid and...

KO CHjCHJK tCHjij

Inhibitors of acetylcholinesterase fall into two groups the reversible carbamate inhibitors such as eserine (physostigmine (8.96)), neostigmine (8.97) and benzylpyrinium (8.98) and the irreversible organophosphorous inhibitors, dyflos (8.99) and ecothiopate (8.100). The carbamates carry a positive charge and are bound at the anionic site (carboxylate ion) of the enzyme and correctly positioned to form a carbamyl enzyme with the serine hydroxyl group at the esteratic site (see Equation 8.36 )....

L 434

Physical descriptors has been presented above. The reason the D L system continues to be used is essentially biochemical. For example D-(+)-glucose (4.25), the enantiomer of glucose found in biological systems, could be known as (2R, 3S, 4R, 5R)-2,3,4,5,6-pentahydroxyhexanal or (2R, 3S, 4R, 5R)-aldohexose, which does not take into account the ring structure of the molecule and the two anomeric forms. It is obviously simpler to refer to D-(+)-glucose. Also the naturally occurring amino acids,...

Log i M uolb log PP 1 C

This equation can model even the case in which activity increases and then levels off as log P increases. The equation is now widely used in QSAR, although it is not so easy to use as the quadratic equation, since the p term has to be obtained by iteration. Figure 5.5 shows a data-set which is clearly modelled better by the bilinear equation than by a parabola. 5.6.2.8 Comparison of slopes and intercepts If two sets of compounds are submitted to the same biological test, and yield rectilinear...

Log tfh 0492t 0585c2445 30 0301 0SS9

ATaft, R.W. (1956) Separation of polar, steric and resonance effects. In Steric Effects in Organic Chemistry, edited by M.S.Newman, pp. 559-675. New York John Wiley. More comprehensive lists of Taft steric parameters can be found in Tute, M.S. (1971) Principles and practice of Hansch analysis A guide to structure activity correlation for the medicinal chemist. In Advances in Drug Research, edited by N.J.Harper and A.B.Simmonds, Vol. 6, pp. 1-77. London Academic Press. Hansch, C. and Leo, A....

LogA log

Partition coefficients for an extensive range of compounds can be found in the literature, together with values of k1 and k2, to convert from one solvent system to another, using Equation 5.1 . It should, however, be noted that the Collander equation holds best when the two solvent systems are similar in nature. Hansch constants for groups attached to aromatic nuclei fall roughly into three categories, depending on the nature of the group already in the ring, and...

Napap

Activity, however, it is not enterally absorbed and rapidly eliminated from the circulation. Variations of the basic structures were performed to improve the pharmacokinetic properties, however, most of them led to a drastic loss in inhibitory activity, without clear improvement in oral bioavailability. From the X-ray crystal structure of the NAPAP-thrombin complex (Figure 8.5) it was obvious that the NAPAP molecule is bound nearly perfectly to thrombin, so that there is only limited space for...

Nystatin

Antifungal activity of the polyenes can be reduced by the addition of sterols or in the presence of sterol-complexing agents. Very few polyenes are used clinically, and two of the most important are nystatin and amphotericin B ((11.121) R H). They show activity against yeasts and fungi but not bacteria. The therapeutic usefulness of the polyenes as a group is limited by their solubility and stability and especially by their toxicity. Polyene methyl esters have been synthesized and this is a...

Occupying group

3-NO2 0.11 -0.01 -0.05 0.11 0.54 -0.36 4-NO 2_0.24 -0.04_0.02 0.16 0.50 -0.39 More comprehensive lists of Hansch substituents constants can be found in Tute, M.S. (1971) Principles and practice of Hansch analysis A guide to structure-activity correlation for the medicinal chemist. In Advances in Drug Research, edited by N.J. Harper and A.B.Simmonds, Vol. 6, pp. 1-77. London Academic Press Hansch, C. and Leo, A. (1979) Substituent Constants for Correlation Analysis in Chemistry and Biology. New...

Only

Single, e.g. ampicillin, chloramphenicol, tetracycline Multiple, e.g. ampicillin+ streptomycin+ sulphonamide Aminoglycoside-aminocyclitols P-lactams Tetracyclines Sulphonamides Trimethoprim Chloramphenicol Erythromycin Fusidic acid Resistance may also be chromosomally mediated 2Multiple resistance genes may be carried on a transposon Another problem concerns the lack of penetration of many drugs into Gramnegative bacteria. On the basis of current knowledge, it would seem logical that any design...

Principal componentFactors

The e term represents the error involved in ignoring column C, and is equal to unity minus the communality of the columns which were considered. Cluster analysis is used to classify results into groups or clusters. Two general procedures will be described, as follows Dendrograms are used to investigate collections of factors to determine which are related and which are independent. A typical example is shown in Table 5.13, which lists ten questions about a collection of shampoos, put to a test...

Prodrugs

7.3 APPLICATION TO PHARMACEUTICAL PROBLEMS 241 7.3.1 Patient acceptability 241 7.4 PHARMACOLOGICAL PROBLEMS 245 7.4.2 Drug distribution 250 7.4.3 Site-specific drug delivery 253 7.4.4 Sustaining drug action 258 7.5 SUMMARY 259 FURTHER READING 259 Although pharmaceutical companies attempt to design and develop new chemical entities using rational and logical processes, very few of these compounds become clinically useful drugs because unpredictable interactions with biological systems reduces...

Rm log

Where tc and to are the retention times of the compound and of a non-retained solute respectively. A range of stationary phases can be used, depending on the nature of the compounds to be chromatographed, to give an appropriate range of Rm or log k' values. For example, a TLC plate may be impregnated with liquid paraffin, and acetone-water mixtures used as For hydrocarbon chains, 0.12 (n-1) is subtracted, where n is the number of bonds between carbons and between carbon and hetero atoms...

Soluble synthetic polymers Viruses and viral envelope products

Parenteral administration is the simplest and most efficient approach for any of the carrier systems, although considerable efforts have been expended to develop systems that will be capable of reaching the blood pool via mucosal epithelia (nasal, pulmonary, buccal intestinal, vaginal, rectal). Transport mechanisms include fluid-phase pinocytosis, paracellular and transcellular diffusion, receptor-mediated transand endo-cytosis, nutrient carrier processes and lymphatic translocation. 2.8.2 Fate...

Substituent Constants for Correlation Analysis in Chemistry and Biology New York John Wiley

Rules from those of classical algebra, and become very protracted when there are a lot of data. Table 5.10 is a typical matrix of QSAR data, and is a series of rows of numbers, each row representing one compound. Each number in a row forms part of a vertical column, and each column represents a specific property, in this case log TM, log BRmax, log kc, Rm or Es. These parameters are defined in Table 5.10. Such a matrix is called an observation matrix, because it contains the raw data upon which...

T

Sequential chemotherapy involves the use of two inhibitors simultaneously on a metabolic chain (Equation 8.6 ) and is employed with the aim of achieving a greater therapeutic effect than by application of either alone. This situation arises when dosage is limited by host toxicity or resistant bacterial strains have emerged. The best known combination is the antibacterial mixture co-trimoxazole, consisting of trimethoprim (dihydrofolate reductase (DHFR) inhibitor) and the sulphonamide...

Tt

Inhibition of an enzyme on occasions leads to formation of a dead-end complex between the enzyme, co-enzyme and inhibitor rather than straightforward interaction between the inhibitor and the enzyme. 5-Fluorouracil inhibits thymidylate synthetase to form a dead-end complex with the enzyme and coenzyme, tetrahydrofolate, so preventing bacterial growth (Equation 8.7 ). Where product build-up progressively decreases the activity of an enzyme on its substrate, then enhancement of product inhibition...

U75875

Adaptation of the hydroxyethylamine dipeptide isostere to mimic the Phe-Pro site has produced inhibitors with selectivity for the retro viral protease (8.81, Ki 0.66 nM). Conversion of the proline to a decahydroisoquinoline nucleus has been very successful in the development of the potent selective HIV protease inhibitor saquinavir (8.82, Ki< 0.12 nM) which has recently gained licensing approval in USA for clinical use. Unlike compound JG-365 (8.83), where the crystal structure has shown a...

UK 69578candmatrilat

Candoxatrilat (8.62, UK 69578), where the (+)-enantiomer is 30-fold more potent than the (-)-enantiomer. Phosphoramidon, a phosphoryl dipeptide of microbial origin, inhibits both thermolysin and MEP and has formed the basis for the development of specific phosphoryl inhibitors of MEP. A phosphonic acid dipeptide containing a P-alanine residue (8.63) has shown selectivity for MEP. A-Phosphonomethyl dipeptide inhibitors such as CGS 24592 (8.64) were based on the observation that the ACE...

Ur OH

9.15.3 Photoactivated prodrugs (Photodynamic Therapy PDT) There is considerable interest in the concept of Photodynamic Therapy which involves the administration of a non-toxic prodrug that can be activated selectively at the tumour site by light of a specific wavelength. This approach has been in use for a number of years for the treatment of psoriasis (PUVA treatment) using 8-methoxypsoralen (9.62). This agent is relatively non-toxic until exposed to UV light when it cross-links DNA at...

X

S-enantiomers in the USA and it has been reported that the reduced dose of the single isomers compared to the racemate resulted in a corresponding reduction in the sedative effects of these agents. Within the dimethylaminoethyloxy ether series of compounds, i.e. derivatives of diphenhydramine (4.116), substitution of one of the phenyl rings or replacement of one ring by a 2-substituted pyridine ring results in the introduction of a chiral centre. The 4-methyl substituted derivative of...

R 0CHrCh R Nch Cn ihjn

Volatile organophosphorus compounds such as sarin (8.101) and tabun (8.102) have been prepared for use as nerve gases in war and other less volatile compounds have been used as insecticides for the spraying of crops. Inhibition of the mammalian or insect enzyme leads to a build-up of acetylcholine and death from accumulated acetylcholine poisoning. Much research has been carried out to find antidotes, for nerve gas poisoning, which could be distributed to the population in the event of war. One...

Quantitative Structureactivity Relationships And Drug Design

5.2 HYDROPHOBICITY PARAMETERS 169 5.2.1 Hydrophobic (Hansch) substituent constants 170 5.2.2 Hydrophobic fragmentai constants 171 5.2.3 Chromatographic hydrophobicity values 172 5.2.4 Aqueous solubility 173 5.3 ELECTRONIC PARAMETERS 173 5.3.1 Hammett constants 174 5.3.2 Inductive substituent constants 177 5.3.3 Taft's substituent constants 178 5.3.4 Hydrogen bonding parameters 178 5.3.5 Whole molecule parameters 179 5.4 STERIC PARAMETERS 179 5.4.1 Substituent parameters 179 5.4.1.1 Taft's...

Nfifi TCJK 26303

Departure from other MEP inhibitors which contain a modified di- (or tri-) peptide backbone, with a critical secondary amide bond and a zinc-chelating ligand. Modification of the C-terminal carboxylic acid functionality of (8.65) to a tetrazole led to a highly potent, non-peptide MEP inhibitor CGS 26303 (8.66). As with ACE inhibitors, these MEP inhibitors are not well absorbed orally, which limits their potential therapeutic usefulness. To improve pharmacokinetic profiles, the inhibitors have...

Drug Chirality And Its Pharmacological Consequences

4.2 DEFINITIONS AND NOMENCLATURE 99 4.2.1 Nomenclature and designation of stereoisomers 103 4.2.2 The nomenclature problem in generic names 111 4.3 BIOLOGICAL ACTIVITY 112 4.3.1 Terminology used in the pharmacological evaluation of stereoisomers 116 4.3.2 Purity of enantiomerically pure drugs 117 4.3.3 Receptor selectivity 119 4.3.4 Quantitative structure activity relationships 120 4.4 PHARMACOKINETIC CONSIDERATIONS 122 4.4.5 Pharmacokinetic parameters 134 4.5 PHARMACODYNAMIC CONSIDERATIONS 135...

J3 L iiiniiioerJiylphosphojiic

Bacteria, possesses significant activity against P-lactamase staphylococcal producers. Its intrinsic potency is, however, less than that of benzylpenicillin against non-P-lactamase staphylococci, and acid instability precludes the oral usage of methicillin. Methicillin was soon followed by ampicillin (11.36), and this was another significant advance, because ampicillin was the first semisynthetic penicillin to possess marked activity against Gram-negative organisms (although Ps. aeruginosa is...

Design Of Antimicrobial Chemotherapeutic Agents

EDWARD G.M.POWER and A.DENVER RUSSELL 11.2 PRODUCTION OF CHEMOTHERAPEUTIC AGENTS 436 11.3 MECHANISM OF ACTION OF CHEMOTHERAPEUTIC AGENTS 438 11.3.1 Inhibitors of cell wall synthesis 438 11.3.2 Membrane-active agents 442 11.3.3 Inhibitors of protein synthesis 442 11.3.4 Inhibitors of nucleic acid synthesis 442 11.3.5 Antibacterial folate inhibitors 445 11.3.6 Conclusions and comments 447 11.4 BACTERIAL RESISTANCE TO CHEMOTHERAPEUTIC AGENTS 447 11.4.1 Enzyme-mediated resistance 447 enzymes 449...

S4 X O habperidol

8.6.2 Acetylcholinesterase inhibitors Acetylcholine is the chemical transmitter released at the nerve endings in the parasympathetic and motor nervous systems following a nervous impulse. After a response from the tissue the acetylcholine is removed by hydrolysis to inert products by acetylcholinesterase (see Equation 8.35 ) in the proximity. Inhibitors of acetylcholinesterase allow a build up of acetylcholine at the nerve endings so that a more prolonged effect is produced which is useful in...

A32531ij4e A75272

Studies on antifungal chemotherapy continue to lag behind those on antibacterial agents. As further information is gleaned as to the structural complexity of and biosynthetic processes in fungal cells, it is hoped that a more logical design of powerful new antifungal compounds can be achieved. Certainly, new azole derivatives can be expected to become increasingly important, but approaches such as that described in Section 11.7.7 may produce clinically useful alternatives. The design of...

Essential and beneficial metals

Bone deformities (Rickets), tetany Anaemia, anorexia Atherosclerosis, cataracts, gall stones Cardiomyopathy, hypothyroidism, polycythaemia, cancer Wilson's disease, intestinal and liver inflammation, haemolysis, hyperglycaemia Contact dermatitis, allergy, lung cancer Anaemia, Menke's kinky hair syndrome Defective glucose metabolism, hyperlipidaemia, corneal opacity Anaemias Haematochromatosis, siderosis, cardiac failure, cancer Anaemia, gout-like lesions, persistent keratinization defects,...

Water

Where only one interaction with the protein occurs, then replacement should be possible unless the water molecule under consideration forms a link in a chain of interacting hydrogen bonded groups from the protein or other water molecules. In this case preservation of the chain may be an important consideration. For two or less interactions with the protein or surrounding system, the bound water may be described as ligand-like and it should be possible to displace it with a favourable energetic...

Copper

Synthesis Methisazone

Caeruloplasmin Serum albumin LMM Cu2+ (Metallothionein) complexes Cu(H2O) 6 2+ Zinc a2-macroglobulin Serum albumin LMM Zn2+ Metallothionein complexes Zn(H2O) 6 2+ LMM Low molecular mass complexes. Table 13.6 Predominant copper complexes identified in blood plasma by computer speciation analysis. Complex species Percentage of total Cu(II) in the low molecular The analysis of the concentration and distribution of the different chemical forms (species) of a metal in a system is known as...

From Page and Jencks 1971 by permission

We consider first the effect of solvation on translational and rotational entropies. There will be some loss in translational and rotational entropy on solution. For a non-polar molecule, the magnitude of this loss is 10 e.u. or a TAS contribution of 3 kcal mol at blood temperature when the same reference concentration is taken in the gas and liquid phases. The translational and rotational entropy loss on binding to a receptor site is thus expected to be not very different between...

Distomers Of Dextropropoxyphene

Levopropoxyphene

Where KEu and KDiS are equilibrium dissociation constants for the eutomer and distomer respectively. A plot of Eudismic Index versus pKEu, for a homologous or congeneric series of isomeric pairs of compounds generally yields a straight line. The slope of which is positive and is known as the Eudismic Affinity Quotient (EAQ) which is a quantitative measure of the stereoselectivity within the compound series for a particular biological effect. It is important to appreciate that such terminology...

LiLiirioniiit

Cephalosporin dihydrothiazine ring is replaced by a methylene group (cf. carbapenems, Section 11.5.5.2). Loracarbef is highly active against Gram-positive bacteria, including staphylococci, but shows poor activity against Gram-negative bacteria. 11.6 DESIGN OF OTHER ANTIBACTERIAL AGENTS Whilst it is probably true to state that P-lactam antibiotics occupy the greatest attention in the treatment of bacterial infecctions, it would be incorrect to imply that other antimicrobial agents do not have...

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Bacteria must synthesize folate because they are unable to absorb preformed folate. PAB, an essential constituent in folate metabolism, and sulphonamides have similar chemical structures. Diaminopyrimidines structurally dissimilar from folic acid have been known for some time to be antagonists of folic acid. The best known example, trimethoprim (11.22), is a potent inhibitor of dihydrofolate reductase (DHFR), the enzyme responsible for converting dihydrofolate (11.21) to tetrahydrofolate...

The Design Of Drug Delivery Systems

2.3 PHYSICO-CHEMICAL FACTORS INFLUENCING DRUG BIOAVAILABILITY 31 2.4 INFLUENCE OF ROUTE OF ADMINISTRATION AND TYPE OF DOSAGE 2.5 FORMULATION FACTORS 35 2.5.3 Soft gelatin capsules 37 2.5.5 Hard gelatin capsules 37 2.6 DRUG DELIVERY TO THE LUNG 38 2.6.1 Therapeutic aerosol generation and particle fate 39 2.6.2 Metered dose inhalers (MDIs) 40 2.6.4 Dry powder inhalers (DPIs) 41 2.6.5 Pulmonary drug selectivity and prolongation of therapeutic effects 42 2.6.5.2 Polyamine active transport system 42...

Bioinorganic Chemistry And Its Pharmaceutical Applications

13.3 METAL COORDINATION CHEMISTRY 516 13.3.1 General aspects 516 13.3.2 Metal-ligand specificity 517 13.3.2.1 Complex stability 517 13.3.2.2 The hard and soft acid and base approach (HSAB) 518 13.3.2.4 In vivo complexing and metabolic specificity 520 13.4 PHARMACOLOGICAL AND PHARMACEUTICAL CONSIDERATIONS 521 13.5 METALS AS THE MODUS OPERANDI OF DRUGS 522 13.5.1.1 Bismuth in the treatment of peptic 13.5.1.2 Metals as anti-cancer agents 523 13.5.1.3 Copper and rheumatoid arthritis 525 13.6 DRUGS...

Metabolism Of L Dopa

Dopamine Metbolism Cns

8.6.4.2 Peripheral aromatic amino acid decarboxylase (AADC) inhibitors Noradrenaline is synthesized at the nerve endings of the postganglionic fibre by a series of reactions from tyrosine (see Equation 8.44 ). Inhibitors of AADC have been synthesized as potential antihypertensive drugs on the basis that a decrease in the biosynthesis of noradrenaline would deplete noradrenaline stores at the nerve endings and lead to a decrease in blood pressure. Although many reversible inhibitors of the...

Intermolecular Forces And Molecular Modelling

3.2 MOLECULAR INTERACTIONS 53 3.2.1 Electrostatic interactions 53 3.2.2 The hydrogen bond 54 3.2.3 van der Waals interactions 56 3.2.4 Exchange repulsion 56 3.3 FREE ENERGIES OF INTERACTION GAS PHASE AND SOLUTION 56 3.3.1 Entropy and free energy contributions in the 3.3.2 Entropy and free energy contributions in solution 57 3.3.3 Electrostatic interactions in solution 58 3.3.4 van der Waals interactions in solution and the hydrophobic effect 58 3.3.5 Some experimental observations...

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Figure 8.1 Definition of binding sites for substrates and inhibitors. Figure 8.2 Mechanism of action of serine proteases. Figure 8.2 Mechanism of action of serine proteases. (iv) Hydrolysis of the acyl-enzyme by catalytic addition of water produces the N-terminal carboxylic acid fragment of the peptide and the free enzyme which is then ready to repeat the cycle. Human neutrophil and leucocyte elastases are members of a subfamily of proteases released in response to various inflammatory stimuli...

Neurotransmitters Agonists And Antagonists

Agonist Drug

ROBERT D.E.SEWELL, RICHARD A.GLENNON, MALGORZATA DUKAT, HOLGER STARK, WALTER SCHUNACK and PHILIP G.STRANGE 10.1 OVERVIEW 388 ROBERT D.E.SEWELL 388 10.1.1.3 Neuronal signal effectors 391 FURTHER READING 391 10.2 SEROTONIN RECEPTORS AND LIGANDS 391 10.2.2 Subpopulations of 5-HT Receptors 392 10.2.3 Receptor populations and ligands 394 10.2.3.9 5-HT5, 5-HT6 and 5-HT7 407 10.2.4 Possible applications of 5-HT agonists and antagonists 407 10.2.5 Epilogue 408 FURTHER READING 408 10.3 HISTAMINE...

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Stereoisomers Acetylcholine

Differential stereoselectivity has also been observed with agonists at the histamine receptor subtypes. The introduction of a methyl group a to the amino group in histamine results in the chiral molecule a-methylhistamine 4.60 . Examination of the activity of the enantiomers of a-methylhistamine at the three histamine receptor subtypes yields eudismic ratios R S of 1, 0.6 and approximately 100 at H1, H2 and H3 receptors respectively. The H1-receptor showing no stereoselectivity, the H2-receptor...

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Australia Canada China France Germany India Japan Luxembourg Malaysia The Netherlands Russia Singapore Switzerland Thailand Copyright 1998 OPA Overseas Publishers Association Amsterdam B.V. Published under license under the Harwood Academic Publishers imprint, part of The Gordon and Breach Publishing Group. First Edition published 1983 This edition published in the Taylor amp Francis e-Library, 2005. To purchase your own copy of this or any of Taylor amp Francis or Routledges's collection of...