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)

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)

Potent and Selective Agonists of Sphingosine 1‑Phosphate 1 (S1P₁): Discovery and SAR of a Novel Isoxazole Based Series

Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P_1–5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P₁, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P₁. Isoxazole <b>6d</b> demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis

Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7‑(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]‑9<i>H</i>‑carbazole-1-carboxamide (BMS-935177)

Bruton’s tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure–activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydro­quinazolin-3-yl)­phenyl]-9<i>H</i>-carbazole-1-carboxamide <b>6</b> (BMS-935177) was selected to advance into clinical development

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

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