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
Preparation of the title compound (2) by use of Stille couplings and a Kröhnke pyridine synthesis is described. By application of the Stille coupling reaction, preparation and functionalization of quater- and quinquepyridines 26, 27, and 28 were achieved. Elaboration of quinquepyridine 27 to the pyridinium salt 30 bearing a protected enal allowed for the synthesis of 2 by a one-pot deprotection/Kröhnke reaction in nine steps from 4,4'-bipyridine. Use of the Kröhnke pyridine synthesis has been applied to prepare sexipyridine dibromide 19, but attempts to induce a macrocyclization via metal-mediated (Pd/Ni/Cu) aryl-aryl coupling procedures proved unsuccessful. Acetylene-bridged sexipyridines 3a and 3b incorporating 2,2'-bipyridine units proved to be inaccessible via sp-sp(2) or sp-sp coupling protocols.
