Evolution of a Scale-Up Synthesis to a Potent GluN2B Inhibitor and Its Prodrug

This paper describes the efficient scale-up synthesis of the potent negative allosteric glutamate N2B (GluN2B) inhibitor <b>1</b> (BMS-986169), which relies upon a stereospecific S_N2 alkylation strategy and a robust process for the preparation of its phosphate prodrug <b>28</b> (BMS-986163) from parent <b>1</b> using POCl₃. A deoxyfluorination reaction employing bis­(2-methoxyethyl)­aminosulfur trifluoride (Deoxo-Fluor) is also used to stereospecifically introduce a fluorine substituent. The optimized routes have been demonstrated to provide APIs suitable for toxicological studies in vivo

Improving the Pharmacokinetic and CYP Inhibition Profiles of Azaxanthene-Based Glucocorticoid Receptor ModulatorsIdentification of (<i>S</i>)‑5-(2-(9-Fluoro-2-(4-(2-hydroxypropan-2-yl)phenyl)‑5<i>H</i>‑chromeno[2,3‑<i>b</i>]pyridin-5-yl)-2-methylpropanamido)‑<i>N</i>‑(tetrahydro‑2<i>H</i>‑pyran-4-yl)-1,3,4-thiadiazole-2-carboxamide (BMS-341)

An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds <b>1a</b> and <b>1b</b> led to the identification of <b>5</b> (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound <b>5</b> showed significant improvements in pharmacokinetic properties and, unlike compounds <b>1a</b>–<b>b</b>, displayed a linear, dose-dependent pharmacokinetic profile in rats. When tested in a chronic model of adjuvant-induced arthritis in rat, the ED₅₀ of <b>5</b> (0.9 mg/kg) was superior to that of both <b>1a</b> and <b>1b</b> (8 and 17 mg/kg, respectively)

Diphenylpyridylethanamine (DPPE) Derivatives as Cholesteryl Ester Transfer Protein (CETP) Inhibitors

A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead <b>7</b> generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea <b>15d</b>, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of <b>15d</b> was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide <b>20</b> with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound <b>20</b> demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures

Discovery and Structure–Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P₁)

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates a multitude of physiological processes such as lymphocyte trafficking, cardiac function, vascular development, and inflammation. Because of the ability of S1P₁ receptor agonists to suppress lymphocyte egress, they have great potential as therapeutic agents in a variety of autoimmune diseases. In this article, the discovery of selective, direct acting S1P₁ agonists utilizing an ethanolamine scaffold containing a terminal carboxylic acid is described. Potent S1P₁ agonists such as compounds <b>18a</b> and <b>19a</b> which have greater than 1000-fold selectivity over S1P₃ are described. These compounds efficiently reduce blood lymphocyte counts in rats through 24 h after single doses of 1 and 0.3 mpk, respectively. Pharmacodynamic properties of both compounds are discussed. Compound <b>19a</b> was further studied in two preclinical models of disease, exhibiting good efficacy in both the rat adjuvant arthritis model (AA) and the mouse experimental autoimmune encephalomyelitis model (EAE)

Discovery of 6‑Fluoro-5‑(<i>R</i>)‑(3‑(<i>S</i>)‑(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4<i>H</i>)‑yl)-2-methylphenyl)-2‑(<i>S</i>)‑(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro‑1<i>H</i>‑carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton’s Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers

Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure–activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, <b>14f</b> (BMS-986142) was advanced into clinical studies