ABSTRACT
We have discovered that introduction of appropriate amino acid derivatives at P'2 position improved the binding potency of P3-capped alpha-ketoamide inhibitors of HCV NS3 serine protease. X-ray crystal structure of one of the inhibitors (43) bound to the protease revealed the importance of the P'2 moiety.
Subject(s)
Hepacivirus/chemistry , Serine Proteinase Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Binding Sites , Crystallography, X-Ray , Molecular Structure , Protein Binding , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistryABSTRACT
The C3 phenylpropyl side chain of N-phenylazetidinones related to SCH 56524 was modified by replacing the hydroxymethylene with various isoelectronic or isosteric groups. Modifications at the 3' position led to less-active compounds; however, modifications at the 1' position provided compounds with improved cholesterol absorption inhibitory activity. An enantioselective route for the synthesis of C3 1'-sulfur-substituted azetidinones and the development of structure-activity relationships for this series of compounds are presented.
Subject(s)
Anticholesteremic Agents/chemical synthesis , Azetidines/chemical synthesis , Animals , Anticholesteremic Agents/pharmacology , Azetidines/chemistry , Azetidines/pharmacokinetics , Azetidines/pharmacology , Bile/metabolism , Cholesterol/metabolism , Intestinal Absorption/drug effects , Macaca fascicularis , Male , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Tetracyclic guanines have been shown to be potent and selective inhibitors of the cGMP-hydrolyzing enzymes PDE1 and PDE5. In general, these compounds are inactive or only weakly active as inhibitors of PDE3, which is a major isozyme involved in cAMP hydrolysis. Structure-activity relationships are developed at N-1, C-2, N-3, and N-5 on the core nucleus. Compound 31, with an IC50 of 70 pM, is the most potent inhibitor of PDE1, while 50, with an IC50 of 4 nM, is the most potent inhibitor of PDE5. Compounds 20, 22, 30, and 50 are potent dual inhibitors with IC50 values below 30 nM for both PDE1 and PDE5. Compounds 12, 20, and 28 reduced blood pressure by more than 45 mmHg when administered orally at 10 mg/kg to the spontaneously hypertensive rat (SHR).
