Discovery of ((<i>S</i>)-5-(Methoxymethyl)-7-(1-methyl-1<i>H</i>-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-<i>a</i>]pyrimidin-6-yl)((<i>S</i>)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone As a Potent and Selective I_Kur Inhibitor

Previously disclosed dihydropyrazolopyrimidines are potent and selective blockers of I_Kur current. A potential liability with this chemotype is the formation of a reactive metabolite which demonstrated covalent binding to protein in vitro. When substituted at the 2 or 3 position, this template yielded potent I_Kur inhibitors, with selectivity over <i>h</i>ERG which did not form reactive metabolites. Subsequent optimization for potency and PK properties lead to the discovery of ((<i>S</i>)-5-(methoxymethyl)-7-(1-methyl-1<i>H</i>-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo­[1,5-<i>a</i>]­pyrimidin-6-yl)­((<i>S</i>)-2-(3-methylisoxazol-5-yl)­pyrrolidin-1-yl)­methanone (<b>13j</b>), with an acceptable PK profile in preclinical species and potent efficacy in the preclinical rabbit atrial effective refractory period (AERP) model

Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of <i>N</i>‑[(1<i>R</i>)‑1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)­phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)­benzamide (BMS-795311)

Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound <b>10g</b> is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (<b>1</b>) in moderately-fat fed hamsters. In contrast to the off-target liabilities with <b>1</b>, no blood pressure increase was observed with <b>10g</b> in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound <b>10g</b> was advanced into preclinical safety studies