9 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 a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing
The
discovery of a back-up to the hepatitis C virus NS3 protease inhibitor
asunaprevir (<b>2</b>) is described. The objective of this work
was the identification of a drug with antiviral properties and toxicology
parameters similar to <b>2</b>, but with a preclinical pharmacokinetic
(PK) profile that was predictive of once-daily dosing. Critical to
this discovery process was the employment of an ex vivo cardiovascular
(CV) model which served to identify compounds that, like <b>2</b>, were free of the CV liabilities that resulted in the discontinuation
of BMS-605339 (<b>1</b>) from clinical trials. Structure–activity
relationships (SARs) at each of the structural subsites in <b>2</b> were explored with substantial improvement in PK through modifications
at the P1 site, while potency gains were found with small, but rationally
designed structural changes to P4. Additional modifications at P3
were required to optimize the CV profile, and these combined SARs
led to the discovery of BMS-890068 (<b>29</b>)