Synthesis and Evaluation of (Pyridylmethylene

May 19, 2005 - 37a, E, 0, 3, nd, nd, 4060. 38a, E, 67, nd, 159, 96, nd, 1.7 ... 1 mg/mL of protein; substrate androstenedione, 500 nM.jIC50 CYP11B1/IC...
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J. Med. Chem. 2005, 48, 4489

4489

Additions and Corrections 2005, Volume 48 Sarah Ulmschneider, Ursula Mu 1 ller-Vieira, Christian D. Klein, Iris Antes, Thomas Lengauer, Rolf W. Hartmann*: Synthesis and Evaluation of (Pyridylmethylene)tetrahydronaphthalenes/-indanes and Structurally Modified Derivatives: Potent and Selective Inhibitors of Aldosterone Synthase Pages 1567 and 1568. In Tables 2 and 3, the column of values for the % inhibition for human CYP17 and the columns of values for IC50 for V79 11B1 hCP11B1 and V79 11B2 hCYP11B2 were swapped with one another. The correct versions of both tables are shown below. Table 2. 4-Pyridylmethylenetetrahydronaphthalenes and -indanes: Inhibition of Human Adrenal CYP11B1 and CYP11B2, Human CYP17, and Human CYP19 in Vitro

% inhibition compd

X

isomer

2a 2b 4a 6a 6b 8a 8b 10a 10b 12a 12b 14a 14b 16a 16b 18a 22a 22b ketoconazole fadrozole

H H H 5-F 5-F 5-Cl 5-Cl 5-Br 5-Br 5-OMe 5-OMe 6-OMe 6-OMe 6-OMe 6-OMe 6,7-di-OMe 6-Me 6-Me

E Z E E Z E Z E Z E Z E Z E Z E E Z

IC50 (nM)

human hCYP11B2a,b

human CYP17c,d

V79 11B1 hCYP11B1e,f

V79 11B2 hCYP11B2e,g

human CYP19h,i

55 nd 54 37 77 38 37 17 40 11 13 31 36 26 24 29 41 46 36 68

8 18 15 15 29 18 36 24 56 59 55 22 56 3 26 11 4 8 40 5

nd 1315 282 380 257 243 1122 948 877 nd nd nd nd nd nd nd nd nd 224 10

nd 931 143 1098 34 1515 301 2640 484 nd nd nd nd nd nd nd nd nd 81 1

6700 12730 650 1550 800 5430 1990 >36000 3400 3960 3720 800 1010 280 770 90 1280 1710 nd 30

selectivity factorj 1.4 2.0 0.3 7.6 0.2 3.7 0.4 1.8

2.8 10

a Mean value of four determinations, standard deviation less than 10%. b S. pombe expressing human CYP11B2; substrate deoxycorticosterone, 100 nM; inhibitor, 500 nM. c Mean value of four determinations, standard deviation less than 10%. d E. coli expressing human CYP17; 5 mg/mL of protein; substrate progesterone, 2.5 µM; inhibitor, 2.5 µM. e Mean value of four determinations, standard deviation less than 20%. nd ) not determined. f Hamster fibroblasts expressing human CYP11B1; substrate deoxycorticosterone, 100 nM. g Hamster fibroblasts expressing human CYP11B2; substrate deoxycorticosterone, 100 nM. h Mean value of four determinations, standard deviation less than 5%. nd ) not determined. i Human placental CYP19; 1 mg/mL of protein; substrate androstenedione, 500 nM. j IC50 CYP11B1/IC50 CYP11B2.

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J. Med. Chem. 2005, 48, 4490

Table 3. Structural Modifications of the Title Compounds: Inhibition of Human Adrenal CYP11B1 and CYP11B2, Human CYP17, and Human CYP19 in Vitro

% inhibition compd

isomer

27a 27b 28a 28b 29a 29b 30a 30b 31a 31b 32 33 34 35 36a 36b 37a 38a ketoconazole fadrozole

E Z E Z E Z E Z E Z

E Z E E

IC50 (nM)

human hCYP11B2a,b

human CYP17c,d

V79 11B1 hCYP11B1e,f

V79 11B2 hCYP11B2e,g

human CYP19h,i

18 17 72 14 0 0 60 91 0 0 0 5 6 32 47 15 0 67 36 68

17 5 6 0 14 31 57 65 20 14 6 9 5 22 13 41 3 nd 40 5

nd nd 3179 nd nd nd 1129 374 nd nd nd nd nd nd nd nd nd 159 224 10

nd nd 27 nd nd nd 58 26 nd nd nd nd nd nd nd nd nd 96 81 1

4330 4830 7450 790 >36000 >36000 720 1940 >36000 >36000 4810 3630 2740 100 3680 2800 4060 nd nd 30

selectivity factorj

118

19.5 14.4

1.7 2.8 10

a Mean value of four determinations, standard deviation less than 10%. b S. pombe expressing human CYP11B2; substrate deoxycorticosterone, 100 nM; inhibitor, 500 nM. c Mean value of four determinations, standard deviation less than 10%. d E. coli expressing human CYP17; 5 mg/mL of protein; substrate progesterone, 2.5 µM; inhibitor, 2.5 µM. e Mean value of four determinations, standard deviation less than 20%. nd ) not determined. f Hamster fibroblasts expressing human CYP11B1; substrate deoxycorticosterone, 100 nM. g Hamster fibroblasts expressing human CYP11B2; substrate deoxycorticosterone, 100 nM. h Mean value of four determinations, standard deviation less than 5%. nd ) not determined. i Human placental CYP19; 1 mg/mL of protein; substrate androstenedione, 500 nM. j IC50 CYP11B1/IC50 CYP11B2.

JM058022P 10.1021/jm058022p Published on Web 05/19/2005