Improving the pharmacokinetic and CYP inhibition profiles of azaxanthene-based glucocorticoid receptor modulators-identification of (S)-5-(2-(9-fluoro-2-(4-(2-hydroxypropan-2-yl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanamido)-N-(tetrahydro-2H-pyran-4-yl)-1,3,4-thiadiazole-2-carboxamide (BMS-341).

Autor:	Yang MG; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Dhar TG; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Xiao Z; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Xiao HY; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Duan JJ; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Jiang B; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Galella MA; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Cunningham M; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Wang J; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Habte S; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Shuster D; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., McIntyre KW; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Carman J; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Holloway DA; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Somerville JE; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Nadler SG; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Salter-Cid L; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Barrish JC; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Weinstein DS; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2015 May 28; Vol. 58 (10), pp. 4278-90. Date of Electronic Publication: 2015 May 07.
DOI:	10.1021/acs.jmedchem.5b00257
Abstrakt:	An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds 1a and 1b led to the identification of 5 (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound 5 showed significant improvements in pharmacokinetic properties and, unlike compounds 1a-b, displayed a linear, dose-dependent pharmacokinetic profile in rats. When tested in a chronic model of adjuvant-induced arthritis in rat, the ED50 of 5 (0.9 mg/kg) was superior to that of both 1a and 1b (8 and 17 mg/kg, respectively).
Databáze:	MEDLINE
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