Introduction of a carboxylic acid group into pyrazolylpyridine derivatives increased selectivity for inhibition of the 20-HETE synthase CYP4A11/4F2

Abstract

20-Hydroxyeicosatetraenoic acid (20-HETE) is a lipid mediator and one of the major arachidonic acid metabolites whose formation is mainly catalyzed by the enzymes cytochrome P450 (CYP) 4F2 and CYP4A11. Several studies have suggested that 20-HETE is involved in the pathogenesis of renal diseases, including diabetic nephropathy and autosomal dominant polycystic kidney disease, and we previously reported compound 1 as a dual inhibitor of CYP4A11/4F2 with therapeutic potential against renal fibrosis. Subsequent studies revealed that compound 1, the dual CYP4A11/4F2 inhibitor, however, exhibited low selectivity over another CYP4F subtype, CYP4F22, which catalyzes ω-hydroxylation of ultra-long-chain fatty acids (ULCFAs); ULCFAs are important for the formation of acylceramides, which play a role in skin barrier formation. Therefore, we sought to develop a CYP4A11/4F2 inhibitor that would show greater CYP4A11/4F2 selectivity against CYP4F22, to avoid potential dermatological side effects. We re-evaluated a series of compounds from our 20-HETE program and identified pyrazolylpyridine derivatives containing a carboxylic acid group showing only weak CYP4F22 inhibition. Subsequent optimization studies from these derivatives led to identification of compound 15, which showed CYP4A11/4F2 inhibition with improved selectivity against CYP4F22. Compound 15 inhibited 20-HETE production in both human and rat renal microsomes and did not inhibit ω-hydroxylation of ULCFAs in human keratinocytes. Compound 15 also significantly inhibited renal 20-HETE production after oral administration.