DISCOVERY AND SYNTHESIS OF METHYL [2-(PHENYLMETHYL)BENZOYL]-1H-PYRROLE-3-CARBOXYLATE (FPL-64176) AND ANALOGS - THE 1ST EXAMPLES OF A NEW CLASS OF CALCIUM-CHANNEL ACTIVATOR
Ajg. Baxter et al., DISCOVERY AND SYNTHESIS OF METHYL [2-(PHENYLMETHYL)BENZOYL]-1H-PYRROLE-3-CARBOXYLATE (FPL-64176) AND ANALOGS - THE 1ST EXAMPLES OF A NEW CLASS OF CALCIUM-CHANNEL ACTIVATOR, Journal of medicinal chemistry, 36(19), 1993, pp. 2739-2744
Methyl 2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate, FPL 64176 (1
), is the first example of a new class of calcium channel activator (C
CA) that does not act on any of the well-defined calcium channel modul
ator receptor sites, as typified by verapamil, diltiazem, and the dihy
dropyridines. The potent activity of 1, having the 2-(phenylmethyl)ben
zoyl substituent, was predicted using QSAR on an initial set of less p
otent benzoylpyrroles. When compared to the CCA Bay K 8644, 1 has simi
alr potency on calcium uptake into GH3 cells (both have EC50 approxima
tely 0.015 muM) but is appreciably more potent functionally at increas
ing contractility in a guinea pig atria preparation (1 has EC50 = 0.04
9 muM vs Bay K 8644 EC50 = 1.95 muM). 1 is an achiral, pharmacological
ly clean agonist with no demonstrable partial agonist properties and p
ossesses appreciably higher efficacy than Bay K 8644. It should theref
ore become a useful biochemical and pharmacological tool for the study
of calcium channels in many cell types.