Discovery of Tetralones as Potent and Selective Inhibitors of Acyl-CoA:Diacylglycerol Acyltransferase 1

Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) plays an important role in triglyceride synthesis and is a target of interest for the treatment of metabolic disorders. Herein we describe the structure–activity relationship of a novel tetralone series of DGAT1 inhibitors and our strategies for overcoming genotoxic liability of the anilines embedded in the chemical structures, leading to the discovery of a candidate compound, (<i>S</i>)-2-(6-(5-(3-(3,4-difluorophenyl)­ureido)­pyrazin-2-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)­acetic acid (GSK2973980A, <b>26d</b>). Compound <b>26d</b> is a potent and selective DGAT1 inhibitor with excellent DMPK profiles and <i>in vivo</i> efficacy in a postprandial lipid excursion model in mice. Based on the overall biological and developability profiles and acceptable safety profiles in the 7-day toxicity studies in rats and dogs, compound <b>26d</b> was selected as a candidate compound for further development in the treatment of metabolic disorders

Optimization of a Novel Series of TRPV4 Antagonists with In Vivo Activity in a Model of Pulmonary Edema

High-throughput screening and subsequent hit optimization identified 1-piperidinylbenzimidazoles, exemplified by compound <b>1</b>, as TRPV4 inhibitors. Lead optimization identified potent TRPV4 blocker <b>19</b>, which has good target activity and pharmacokinetic properties. Inhibitor <b>19</b> was then profiled in an in vivo rat model, demonstrating its ability to inhibit TRPV4-mediated pulmonary edema

Identification of Purines and 7‑Deazapurines as Potent and Selective Type I Inhibitors of Troponin I‑Interacting Kinase (TNNI3K)

A series of cardiac troponin I-interacting kinase (TNNI3K) inhibitors arising from 3-((9<i>H</i>-purin-6-yl)­amino)-<i>N</i>-methyl-benzenesulfonamide (<b>1</b>) is disclosed along with fundamental structure–function relationships that delineate the role of each element of <b>1</b> for TNNI3K recognition. An X-ray structure of <b>1</b> bound to TNNI3K confirmed its Type I binding mode and is used to rationalize the structure–activity relationship and employed to design potent, selective, and orally bioavailable TNNI3K inhibitors. Identification of the 7-deazapurine heterocycle as a superior template (vs purine) and its elaboration by introduction of C4-benzenesulfonamide and C7- and C8–7-deazapurine substituents produced compounds with substantial improvements in potency (>1000-fold), general kinase selectivity (10-fold improvement), and pharmacokinetic properties (>10-fold increase in poDNAUC). Optimal members of the series have properties suitable for use in <i>in vitro</i> and <i>in vivo</i> experiments aimed at elucidating the role of TNNI3K in cardiac biology and serve as leads for developing novel heart failure medicines

Identification of Purines and 7‑Deazapurines as Potent and Selective Type I Inhibitors of Troponin I‑Interacting Kinase (TNNI3K)

A series of cardiac troponin I-interacting kinase (TNNI3K) inhibitors arising from 3-((9<i>H</i>-purin-6-yl)­amino)-<i>N</i>-methyl-benzenesulfonamide (<b>1</b>) is disclosed along with fundamental structure–function relationships that delineate the role of each element of <b>1</b> for TNNI3K recognition. An X-ray structure of <b>1</b> bound to TNNI3K confirmed its Type I binding mode and is used to rationalize the structure–activity relationship and employed to design potent, selective, and orally bioavailable TNNI3K inhibitors. Identification of the 7-deazapurine heterocycle as a superior template (vs purine) and its elaboration by introduction of C4-benzenesulfonamide and C7- and C8–7-deazapurine substituents produced compounds with substantial improvements in potency (>1000-fold), general kinase selectivity (10-fold improvement), and pharmacokinetic properties (>10-fold increase in poDNAUC). Optimal members of the series have properties suitable for use in <i>in vitro</i> and <i>in vivo</i> experiments aimed at elucidating the role of TNNI3K in cardiac biology and serve as leads for developing novel heart failure medicines