4 research outputs found
Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor
The
design and synthesis of potent, tripeptidic acylsulfonamide
inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl
amino acid at P1 are described. A cocrystal structure of <b>18</b> with a NS3/4A protease complex suggests the presence of a H-bond
between the polarized C–H of the CHF<sub>2</sub> moiety and
the backbone carbonyl of Leu135 of the enzyme. Structure–activity
relationship studies indicate that this H-bond enhances enzyme inhibitory
potency by 13- and 17-fold compared to the CH<sub>3</sub> and CF<sub>3</sub> analogues, respectively, providing insight into the deployment
of this unique amino acid
Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode
A novel series of pyrrolidine-containing
GPR40 agonists is described
as a potential treatment for type 2 diabetes. The initial pyrrolidine
hit was modified by moving the position of the carboxylic acid, a
key pharmacophore for GPR40. Addition of a 4-<i>cis</i>-CF<sub>3</sub> to the pyrrolidine improves the human GPR40 binding <i>K</i><sub>i</sub> and agonist efficacy. After further optimization,
the discovery of a minor enantiomeric impurity with agonist activity
led to the finding that enantiomers <b>(</b><i><b>R,R</b></i><b>)-68</b> and <b>(</b><i><b>S,S</b></i><b>)-68</b> have differential effects on the radioligand
used for the binding assay, with <b>(</b><i><b>R,R</b></i><b>)-68</b> potentiating the radioligand and <b>(</b><i><b>S,S</b></i><b>)-68</b> displacing
the radioligand. Compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b> activates both
G<sub>q</sub>-coupled intracellular Ca<sup>2+</sup> flux and G<sub>s</sub>-coupled cAMP accumulation. This signaling bias results in
a dual mechanism of action for compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b>, demonstrating glucose-dependent insulin and GLP-1 secretion in
vitro. In vivo, compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b> significantly lowers
plasma glucose levels in mice during an oral glucose challenge, encouraging
further development of the series
Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists
G protein-coupled
receptor 40 (GPR40) has become an attractive
target for the treatment of diabetes since it was shown clinically
to promote glucose-stimulated insulin secretion. Herein, we report
our efforts to develop highly selective and potent GPR40 agonists
with a dual mechanism of action, promoting both glucose-dependent
insulin and incretin secretion. Employing strategies to increase polarity
and the ratio of sp<sup>3</sup>/sp<sup>2</sup> character of the chemotype,
we identified BMS-986118 (compound <b>4</b>), which showed potent
and selective GPR40 agonist activity <i>in vitro</i>. <i>In vivo</i>, compound <b>4</b> demonstrated insulinotropic
efficacy and GLP-1 secretory effects resulting in improved glucose
control in acute animal models
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