title: Novel, potent and orally bioavailable indolizidinone-derived inhibitors of the hepatitis C virus NS3 protease.
abstract: A novel, potent, and orally bioavailable class of product-like inhibitors of the HCV NS3 protease was discovered by constraining the P2-P3 amide bond and the P3 hydrocarbon substituent to the protease-bound conformation. This preorganization was accomplished by incorporation of the P2-P3 amide into a six-membered ring attached to the P2-proline 5-position. Isothermal calorimetric characterization of the role of hydrocarbon substitution of this six-membered ring, upon binding the HCV NS3 protease, was found to be exclusively entropic in nature. The synthesis, preliminary SAR and pharmacokinetic profiling of this compact, indolizidinone-derived scaffold are described.
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA. Michael.Clarke@gilead.com
authors.forename: Michael O
authors.initials: MO
authors.lastname: Clarke
authors.forename: Daniel
authors.initials: D
authors.lastname: Byun
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Chen
authors.forename: Edward
authors.initials: E
authors.lastname: Doerffler
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Leavitt
authors.forename: X Christopher
authors.initials: XC
authors.lastname: Sheng
authors.forename: Cheng Y
authors.initials: CY
authors.lastname: Yang
authors.forename: Choung U
authors.initials: CU
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007212:Indolizines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D004791:Enzyme Inhibitors; D007212:Indolizines; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases