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)

Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P₁ Receptor Modulator in Clinical Trials

Clinical validation of S1P receptor modulation therapy was achieved with the approval of fingolimod (Gilenya, <b>1</b>) as the first oral therapy for relapsing remitting multiple sclerosis. However, <b>1</b> causes a dose-dependent reduction in the heart rate (bradycardia), which occurs within hours after first dose. We disclose the identification of clinical compound BMS-986104 (<b>3d</b>), a novel S1P₁ receptor modulator, which demonstrates ligand-biased signaling and differentiates from <b>1</b> in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model

Identification of Tricyclic Agonists of Sphingosine-1-phosphate Receptor 1 (S1P₁) Employing Ligand-Based Drug Design

Fingolimod (<b>1</b>) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a nonselective S1P receptor agonist, agonism specifically of S1P₁ is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P₁ while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand-based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P₁ with selectivity over S1P₃ and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes. Compound <b>10</b> had the desired pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated maximal efficacy when administered orally in a rat adjuvant arthritis model