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J Med Chem ; 58(11): 4749-70, 2015 Jun 11.
Article in English | MEDLINE | ID: mdl-25953419

ABSTRACT

CYP11B2, the aldosterone synthase, and CYP11B1, the cortisol synthase, are two highly homologous enzymes implicated in a range of cardiovascular and metabolic diseases. We have previously reported the discovery of LCI699, a dual CYP11B2 and CYP11B1 inhibitor that has provided clinical validation for the lowering of plasma aldosterone as a viable approach to modulate blood pressure in humans, as well normalization of urinary cortisol in Cushing's disease patients. We now report novel series of aldosterone synthase inhibitors with single-digit nanomolar cellular potency and excellent physicochemical properties. Structure-activity relationships and optimization of their oral bioavailability are presented. An illustration of the impact of the age of preclinical models on pharmacokinetic properties is also highlighted. Similar biochemical potency was generally observed against CYP11B2 and CYP11B1, although emerging structure-selectivity relationships were noted leading to more CYP11B1-selective analogs.


Subject(s)
Cytochrome P-450 CYP11B2/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/pharmacokinetics , Microsomes, Liver/drug effects , Steroid 11-beta-Hydroxylase/antagonists & inhibitors , Aldosterone/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Corticosterone/pharmacology , Enzyme Inhibitors/chemistry , Imidazoles/pharmacology , Male , Microsomes, Liver/enzymology , Models, Molecular , Molecular Structure , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tissue Distribution
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