Discovery of S3-Truncated, C‑6 Heteroaryl Substituted Aminothiazine β‑Site APP Cleaving Enzyme‑1 (BACE1) Inhibitors

Truncation of the S3 substituent of the biaryl aminothiazine <b>2</b>, a potent BACE1 inhibitor, led to a low molecular weight aminothiazine <b>5</b> with moderate activity. Despite its moderate activity, compound <b>5</b> demonstrated significant brain Aβ reduction in rodents. The metabolic instability of <b>5</b> was overcome by the replacement of the 6-dimethylisoxazole, a metabolic soft spot, with a pyrimidine ring. Thus, truncation of the S3 substituent represents a viable approach to the discovery of orally bioavailable, brain-penetrant BACE1 inhibitors

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine <b>18</b> with 34-fold improved BACE1 inhibitory activity over the lead compound <b>1</b>. The cocrystal structure of <b>18</b> bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide <b>26</b> as a very potent BACE1 inhibitor (IC₅₀ < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose–response studies. Thus, compound <b>26</b> may be useful in testing the amyloid hypothesis of Alzheimer’s disease

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

Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist

BMS-711939 (<b>3</b>) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC₅₀ of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC₅₀ = 4.5 μM) and PPARδ (EC₅₀ > 100 μM) in PPAR-GAL4 transactivation assays. Compound <b>3</b> also demonstrated excellent <i>in vivo</i> efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure–activity relationship (SAR) studies, and <i>in vivo</i> pharmacology of <b>3</b> in preclinical animal models as well as its ADME profile are described

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