Pregnanes

Among the pregnane CYP17 inhibitors, compounds 63-65 (Fig. 6, Table 3, entries 1-3) bearing 20-substituents with moderate to strong dipole properties were more active than ketoco-nazole in inhibiting human CYP17, displaying IC50 values of 16 to 230 nM and 16 to 190 nM for the hydroxylase and lyase activities, respectively [90, 110, 111]. In 2000, Hartman et al. tested several pregneneoximes 66-76 among which some were potent inhibitors of both rat and human CYP17 (Fig. 6, Table 3, entries 4-11) [112]. Compound 66 was effective in vivo and suppressed plasma T concentrations more potently than ketoconazole. The hydroxamic acid derivative 77 (Fig. 6) was not a CYP17 inhibitor [113].

Entry

Compound

CYP17 inhibition (nM)

Ref.

1

63

Human (OHase): 16 Human (lyase): 16

2

64

Human (OHase): 180 Human (lyase): 190

3

65

Human (OHase): 230 Human (lyase): 160

[90, 110, 111, 114]

Rat: 520

4

66

Human: 77 E. colib: 230

5

67

Rat: 140 Human: 180

Rat: a

6

69

Human: 170 E. colib: 520

7

70

Rat: a Human: 100

[112]

Rat: a

8

71

Human: 200 E. colib: 420

9

72

Rat: a Human: 200

10

74

Rat: 300 Human: 300

11

76

Rat: 2760 Human: 270

12

78

Rat: 210 Human: 540

13

79

Rat: 34000 Human: 1520

14

80

Rat: 1200

15

81

Rat: 36000

16

82

Rat: 9670 Human: 970

17

83

Rat: 430 Human: 290

[116]

18

84

Rat: 530 Human: 400

Entry

Compound

CYP17 inhibition (nM)

Ref.

Rat (OHase): 75.8

19

85

[117]

Rat (lyase): 55.8

Table 3. IC50 values for pregnane CYP17 inhibitors. a> 125 |jM; bE. Coli cells coexpressing human CYP17 and NADPH reductase

Table 3. IC50 values for pregnane CYP17 inhibitors. a> 125 |jM; bE. Coli cells coexpressing human CYP17 and NADPH reductase

A difference in the inhibitory potential of rat CYP17 of the aziridinylpregnanes 78-81 was observed between the S-and R-isomers, the S-isomers 78 and 80 being 162 and 30-fold more potent than the R-isomers, respectively (Fig. 7, Table 3, entries 12-15) [115]. However, this finding was not corroborated by later studies that used the human enzyme [116]. The activity of compounds 82-85 (Fig. 7, Table 2, entries 16-19) was also reported [116, 117]. Several fluorinated pregnanes 86-91 and 93 were synthesized in search of greater metabolic stability (Fig. 7, Table 3, entry 20, Table 4). Inhibition of the cynomolgous monkey enzyme at 1 |M, following preincubation with the enzyme with compounds 87-93, is depicted on Table 4[118-122].

NH H

R

= ß-OH

A5; 20S

78

R

= ß-OH

A5; 20R

79

R

= O; A4;

20S

80

R

= O; A4;

20R

81

A14; n = 0; 20R 82 A14; n = 0; 20S 83 n = 1; (21S,21R) 1:1 84

TBDMSO"

CHF2

CHF2

R1 R2

O

Entry

Compound

% Inhibition

Ref.

1

87

61

2

88

60

3

89

61

4

90

94

5

91

85

6

92

60

Table 4. Inhibition of cynomolgous monkey testicular CYP17 by pregnane derivatives, at 1 |iM, following preincubation with enzyme.

93 62

Table 4. Inhibition of cynomolgous monkey testicular CYP17 by pregnane derivatives, at 1 |iM, following preincubation with enzyme.

0 0

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