4 research outputs found
Acyl Guanidine Inhibitors of β‑Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution-Phase Library Synthesis
This report describes the discovery and optimization
of a BACE-1
inhibitor series containing an unusual acyl guanidine chemotype that
was originally synthesized as part of a 6041-membered solid-phase
library. The synthesis of multiple follow-up solid- and solution-phase
libraries facilitated the optimization of the original micromolar
hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand
binding and cell-based functional assay formats. The X-ray structure
of representative inhibitors bound to BACE-1 revealed a number of
key ligand:protein interactions, including a hydrogen bond between
the side chain amide of flap residue Gln73 and the acyl guanidine
carbonyl group, and a cation−π interaction between Arg235
and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous
administration in rats, an acyl guanidine inhibitor with single-digit
nanomolar activity in cells afforded good plasma exposures and a dose-dependent
reduction in plasma Aβ levels, but poor brain exposure was observed
(likely due to Pgp-mediated efflux), and significant reductions in
brain Aβ levels were not obtained
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-dihydroÂquinazolin-3-yl)Âphenyl]-9<i>H</i>-carbazole-1-carboxamide <b>6</b> (BMS-935177) was
selected to advance into clinical development
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
Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3‑Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders
PI3Kδ plays an important role
controlling immune cell function and has therefore been identified
as a potential target for the treatment of immunological disorders.
This article highlights our work toward the identification of a potent,
selective, and efficacious PI3Kδ inhibitor. Through careful
SAR, the successful replacement of a polar pyrazole group by a simple
chloro or trifluoromethyl group led to improved Caco-2 permeability,
reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity
profile while maintaining potency in the CD69 hWB assay. The optimization
of the aryl substitution then identified a 4′-CN group that
improved the human/rodent correlation in microsomal metabolic stability.
Our lead molecule is very potent in PK/PD assays and highly efficacious
in a mouse collagen-induced arthritis model