DISCOVERY AND SYNTHESIS OF METHYL 2,5-DIMETHYL-4-[2-(PHENYLMETHYL)BENZOYL]-1H-PYRROLE-3-CARBOXYLATE (FPL-64176) AND ANALOGS - THE 1ST EXAMPLES OF A NEW CLASS OF CALCIUM-CHANNEL ACTIVATOR

Methyl 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate, FPL 64176 (1), is the first example of a new class of calcium channel activator (CCA) that does not act on any of the well-defined calcium channel modulator receptor sites, as typified by verapamil, diltiazem, and the dihydropyridines. The potent activity of 1, having the 2-(phenylmethyl)benzoyl substituent, was predicted using QSAR on an initial set of less potent benzoylpyrroles. When compared to the CCA Bay K 8644, 1 has simialr potency on calcium uptake into GH3 cells (both have EC50 approximately 0.015 muM) but is appreciably more potent functionally at increasing contractility in a guinea pig atria preparation (1 has EC50 = 0.049 muM vs Bay K 8644 EC50 = 1.95 muM). 1 is an achiral, pharmacologically clean agonist with no demonstrable partial agonist properties and possesses appreciably higher efficacy than Bay K 8644. It should therefore become a useful biochemical and pharmacological tool for the study of calcium channels in many cell types.