2 research outputs found
Selective <i>I</i><sub>Kur</sub> Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5‑[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide
We
have recently disclosed 5-phenyl-<i>N</i>-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)Âquinazolin-4-amine <b>1</b> as a potent <i>I</i><sub>Kur</sub> current blocker
with selectivity versus <i>h</i>ERG, Na and Ca channels,
and an acceptable preclinical PK profile. Upon further characterization <i>in vivo</i>, compound <b>1</b> demonstrated an unacceptable
level of brain penetration. In an effort to reduce the level of brain
penetration while maintaining the overall profile, SAR was developed
at the C2′ position for a series of close analogues by employing
hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)Âquinazolin-2-yl]Âpyridine-3-sulfonamide
(<b>25</b>) was identified as the lead compound in this series.
Compound <b>25</b> showed robust effects in rabbit and canine
pharmacodynamic models and an acceptable cross-species pharmacokinetic
profile and was advanced as the clinical candidate. Further optimization
of <b>25</b> to mitigate pH-dependent absorption resulted in
identification of the corresponding phosphoramide prodrug (<b>29</b>) with an improved solubility and pharmacokinetic profile
Discovery of 5‑Chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1<i>H</i>)‑one (BMS-903452), an Antidiabetic Clinical Candidate Targeting GPR119
G-protein-coupled receptor 119 (GPR119)
is expressed predominantly in pancreatic β-cells and in enteroendocrine
cells in the gastrointestinal tract. GPR119 agonists have been shown
to stimulate glucose-dependent insulin release by direct action in
the pancreas and to promote secretion of the incretin GLP-1 by action
in the gastrointestinal tract. This dual mechanism of action has generated
significant interest in the discovery of small molecule GPR119 agonists
as a potential new treatment for type 2 diabetes. Herein, we describe
the discovery and optimization of a new class of pyridone containing
GPR119 agonists. The potent and selective BMS-903452 (<b>42</b>) was efficacious in both acute and chronic in vivo rodent models
of diabetes. Dosing of <b>42</b> in a single ascending dose
study in normal healthy humans showed a dose dependent increase in
exposure and a trend toward increased total GLP-1 plasma levels