Cushing’s Syndrome: Development of Highly Potent and Selective CYP11B1 Inhibitors of the (Pyridylmethyl)pyridine Type

• Published in: Journal of medicinal chemistry Vol. 56; no. 15; pp. 6022 - 6032
• Main Authors: Emmerich, Juliette, Hu, Qingzhong, Hanke, Nina, Hartmann, Rolf W
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08.08.2013
• Subjects: Animals; Cell Line; Cricetinae; Cushing Syndrome - drug therapy; Cushing Syndrome - enzymology; Cytochrome P-450 CYP11B2 - antagonists & inhibitors; Humans; Liver - metabolism; Models, Molecular; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Quantitative Structure-Activity Relationship; Rats; Steroid 11-beta-Hydroxylase - antagonists & inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm400240r

Potent and selective CYP11B1 inhibitors could be promising therapeutics for the treatment of Cushing’s syndrome. Optimization of Ref 1 (5-((1H-imidazol-1-yl)methyl)-2-phenylpyridine) led to compound 44 (5-((5-methylpyridin-3-yl)methyl)-2-phenylpyridine) with a 50-fold improved IC50 value of 2 nM toward human CYP11B1 and an enhanced inhibition of the rat enzyme (IC50 = 2440 nM) compared to Ref 1 (IC50 > 10000 nM). Furthermore, selectivities over CYP11B2, CYP17, and CYP19 were observed, as well as satisfying metabolic stability not only in human and rat plasma but also in liver S9 fraction. Investigation of cytotoxicity and inhibition of hepatic CYP2A6 and CYP3A4 showed that 44 fulfills first safety criteria and can be considered for further in vivo evaluation in rats.