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 degradation (to allow a build up of the pentapeptides in vivo) in search for compounds as potential non-addictive analgesics. Although many compounds which have been developed are potent MEP inhibitors in vitro, the hope of a therapeutically useful analgesic remains to be realised. Attention has now shifted to another pharmacological aim. The loss of biological activity of ANP is the result of cleavage by MEP at the Cys7-Phe8 bond. Inhibitors which prolong the biological activity of ANP have a potential therapeutic role in the treatment of hypertension and congestive heart failure.

A model of the MEP binding site, based on information from the earlier development of inhibitors of related zinc metallo-proteases such as carboxypeptidase A, thermolysin and ACE has been developed. Using MEP inhibitors with the general structure X-AA1-AA2 (X=zinc complexing ligand, AA1 and AA2=amino acid corresponding to P1' and P2' positions respectively, see 8.59), the optimal amino acid requirements for Si' and S2' subsites, zinc complexing ligands of varying affinity together with the importance of other binding sites have been determined.

Zinc binding ligands. Suitable amino acids or short peptides containing terminal zinc liganding groups such as thiol, carboxyl, phosphoramidate or hydroxamate all show inhibitory activity for MEP. From studies on hydroxamic acids, the position of the zinc-binding group seems critical, the optimal inhibitory potency being obtained when the zinc-binding ligand is separated by a single carbon from the chiral centre of the AAi residue.

S' subsite. This site can accommodate large groups such as cyclohexyl and biphenyl moieties, but optimum inhibitory activity has been observed when benzyl is the side chain substituent on AA1. Introduction of a methyl-, methoxy- or amino-substituent on the phenyl ring does not affect inhibitory potency but nitro- and dimethylamino-substituents reduce potency. The presence rather than the absolute configuration of the AA1 is important, indicating flexibility within the region of the active site containing the S1' subsite and zinc. However, the (^-isomers exhibit greater inhibitory potency.

S2'subsite. The binding requirements of this subsite have been established using the dipeptides Phe-Y or Tyr-Y. Compounds without a side-chain on AA2 (Phe-Gly, Tyr-Gly) or substitution on the alpha carbon with methyl group (Phe-Ala, Tyr-Ala), an aromatic ring or a large hydrophobic residue all show good inhibitory activity, P-alanine or y-aminobutyric acid in the AA2 position also increase inhibitory activity. The SMsomer is the preferred configuration at this subsite.

Positively charged arginine residue. This binds with the C-terminal ionized carboxyl of AA2. The presence of a free terminal carboxylate group in AA2 therefore increases binding between the enzyme and substrate or inhibitor. Inhibitors containing

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