title: Discovery and synthesis of methyl 2,5-dimethyl-4-[2- (phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate (FPL 64176) and analogues: the first examples of a new class of calcium channel activator.
abstract: 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 similar potency on calcium uptake into GH3 cells (both have EC50 approximately 0.015 microM) but is appreciably more potent functionally at increasing contractility in a guinea pig atria preparation (1 has EC50 = 0.049 microM vs Bay K 8644 EC50 = 1.95 microM). 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.
authors.affiliation: Department of Medicinal Chemistry, Fisons plc, Loughborough, Leicestershire, United Kingdom.
authors.forename: A J
authors.initials: AJ
authors.lastname: Baxter
authors.forename: J
authors.initials: J
authors.lastname: Dixon
authors.forename: F
authors.initials: F
authors.lastname: Ince
authors.forename: C N
authors.initials: CN
authors.lastname: Manners
authors.forename: S J
authors.initials: SJ
authors.lastname: Teague
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002120:Calcium Channel Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D009200:Myocardial Contraction / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002120:Calcium Channel Agonists; D011758:Pyrroles; C071658:FPL 64176; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester