A Practical Telescoped Three-Step Sequence for the Preparation of (1<i>R</i>,2<i>R</i>)‑2-(4-Bromobenzoyl)cyclohexanecarboxylic Acid: A Key Building Block Used in One of Our Drug Development Projects

A large-scale, robust telescoped process involving acid chloride generation and Friedel–Crafts acylation followed by hydrolysis of an ester was developed for the manufacture of a homochiral disubstituted cyclohexane. Chromatography was avoided, and instead, crystallization was employed to furnish the pure carboxylic acid. This acid was further used as a key building block for the synthesis of drug candidates via amide bond formation using various amines followed by a Suzuki coupling with a pyrazole pinacol ester. The total synthesis of one of the drug candidates on a multihundred gram scale is described

Discovery of Agonists of Cannabinoid Receptor 1 with Restricted Central Nervous System Penetration Aimed for Treatment of Gastroesophageal Reflux Disease

Agonists of the cannabinoid receptor 1 (CB1) have been suggested as possible treatments for a range of medical disorders including gastroesophageal reflux disease (GERD). While centrally acting cannabinoid agonists are known to produce psychotropic effects, it has been suggested that the CB1 receptors in the periphery could play a significant role in reducing reflux. A moderately potent and highly lipophilic series of 2-aminobenzamides was identified through focused screening of GPCR libraries. Development of this series focused on improving potency and efficacy at the CB1 receptor, reducing lipophilicity and limiting the central nervous system (CNS) exposure while maintaining good oral absorption. Improvement of the series led to compounds having excellent potency at the CB1 receptor and high levels of agonism, good physical and pharmacokinetic properties, and low penetration into the CNS. A range of compounds demonstrated a dose-dependent inhibition of transient lower esophageal sphincter relaxations in a dog model

Design of Selective sPLA₂‑X Inhibitor (−)-2-{2-[Carbamoyl-6-(trifluoromethoxy)‑1<i>H</i>‑indol-1-yl]pyridine-2-yl}propanoic Acid

A lead generation campaign identified indole-based sPLA₂-X inhibitors with a promising selectivity profile against other sPLA₂ isoforms. Further optimization of sPLA₂ selectivity and metabolic stability resulted in the design of (−)-<b>17</b>, a novel, potent, and selective sPLA₂-X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (−)-<b>17</b> was tested in an ApoE^–/– murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA₂-X inhibition on atherosclerosis development. Despite being well tolerated and achieving adequate systemic exposure of mechanistic relevance, (−)-<b>17</b> did not significantly affect circulating lipid and lipoprotein biomarkers and had no effect on coronary function or histological markers of atherosclerosis

Discovery of a Series of Indole‑2 Carboxamides as Selective Secreted Phospholipase A₂ Type X (sPLA₂‑X) Inhibitors

In order to assess the potential of sPLA₂-X as a therapeutic target for atherosclerosis, novel sPLA₂ inhibitors with improved type X selectivity are required. To achieve the objective of identifying such compounds, we embarked on a lead generation effort that resulted in the identification of a novel series of indole-2-carboxamides as selective sPLA2-X inhibitors with excellent potential for further optimization