ABSTRACT
PKCα and PKA have crucial but opposing roles in the regulation of calcium handling within myocytes. Identification of compounds that inhibit PKCα, but not PKA, are potential therapeutic targets for the treatment of heart disease. The synthesis of indolylureas are described, and a compound displaying nanomolar inhibition towards PKCα with significant selectivity over PKA has been identified.
Subject(s)
Protein Kinase C-alpha/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Urea/chemical synthesis , Urea/pharmacology , Cyclic AMP-Dependent Protein Kinases , Heart Diseases/drug therapy , Humans , Urea/chemistryABSTRACT
The discovery of a series of novel and orally efficacious type II calcimimetics, developed from the lead compound 1, is described herein. Compound 22 suppressed plasma PTH levels relative to vehicle when dosed orally in a rat pharmacodynamic model.
Subject(s)
Benzylamines/chemistry , Benzylamines/pharmacology , Parathyroid Hormone/antagonists & inhibitors , Parathyroid Hormone/blood , Receptors, Calcium-Sensing/metabolism , Administration, Oral , Animals , Benzylamines/administration & dosage , Benzylamines/pharmacokinetics , Male , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
(1,1-Dioxo-2H-[1,2,4]benzothiadiazin-3-yl) azolo[1,5-a]pyridine and azolo[1,5-a]pyrimidine derivatives have been investigated as potential anti-HCV drugs. Their synthesis, HCV NS5B polymerase inhibition, and replicon activity are discussed.
