3 research outputs found
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 (IC<sub>50</sub> < 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
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