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

PK/PD Disconnect Observed with a Reversible Endothelial Lipase Inhibitor

Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, <i>N</i>-(3-(3,4-dichlorophenyl)­propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (<b>5</b>; EL IC₅₀ = 61 nM, EL_HDL IC₅₀ = 454 nM). Deck mining identified a related hit, <i>N</i>-(3-(3,4-dichlorophenyl)­propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1<i>H</i>-pyrrole-3-carboxamide (<b>6a</b>; EL IC₅₀ = 41 nM, EL_HDL IC₅₀ = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL). Optimization of compound <b>6a</b> for EL inhibition using HDL as substrate led to <i>N</i>-(4-(3,4<b>-</b>dichlorophenyl)­butan-2-yl)-1-ethyl-4-hydroxy-5-oxo-2,5-dihydro-1<i>H</i>-pyrrole-3-carboxamide (<b>7c</b>; EL IC₅₀ = 148 nM, EL_HDL IC₅₀ = 218 nM) having improved PK over compound <b>6a</b>, providing a tool molecule to test for the ability to increase HDL-cholesterol (HDL-C) levels in vivo using a reversible EL inhibitor. Compound <b>7c</b> did not increase HDL-C in vivo despite achieving plasma exposures targeted on the basis of enzyme activity and protein binding demonstrating the need to develop more physiologically relevant in vitro assays to guide compound progression for in vivo evaluation

Selective <i>I</i>_Kur Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5‑[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide

We have recently disclosed 5-phenyl-<i>N</i>-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)­quinazolin-4-amine <b>1</b> as a potent <i>I</i>_Kur current blocker with selectivity versus <i>h</i>ERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization <i>in vivo</i>, compound <b>1</b> demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2′ position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)­quinazolin-2-yl]­pyridine-3-sulfonamide (<b>25</b>) was identified as the lead compound in this series. Compound <b>25</b> showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of <b>25</b> to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (<b>29</b>) with an improved solubility and pharmacokinetic profile

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

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