title: Aroyl(aminoacyl)pyrroles, a new class of anticonvulsant agents.
abstract: 2-Aroyl-4-(omega-aminoacyl)- (4) and 4-aroyl-2-(omega-aminoacyl)pyrroles (9) represent a new, structurally novel class of anticonvulsant agents. Compounds of type 4 were prepared by Friedel-Crafts acylation of a 2-aroylpyrrole with an omega-chloroacyl chloride followed by displacement of the chloro group by a primary or secondary amine. Compounds of type 9 were prepared by Friedel-Crafts aroylation of a 2-(omega-chloroacyl)pyrrole followed by displacement by an amine. These compounds were active in the mouse and rat maximal electroshock tests but not in the mouse metrazole test. The lead compound, RWJ-37868, 2-(4-chlorobenzoyl)-4-(1-piperidinyl-acetyl)-1,3,5-trimethylpyrrole++ + (4d), showed potency and therapeutic index comparable to those of phenytoin and carbamazepine and greater than those of sodium valproate. This compound blocked bicuculline induced seizures, did not elevate seizure threshold following iv infusion of metrazole, and blocked influx of Ca2+ ions into cerebellar granule cells induced by K+ or veratridine.
authors.affiliation: R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477-0776, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Carson
authors.forename: R J
authors.initials: RJ
authors.lastname: Carmosin
authors.forename: P M
authors.initials: PM
authors.lastname: Pitis
authors.forename: J L
authors.initials: JL
authors.lastname: Vaught
authors.forename: H R
authors.initials: HR
authors.lastname: Almond
authors.forename: J P
authors.initials: JP
authors.lastname: Stables
authors.forename: H H
authors.initials: HH
authors.lastname: Wolf
authors.forename: E A
authors.initials: EA
authors.lastname: Swinyard
authors.forename: H S
authors.initials: HS
authors.lastname: White
mesh_terms: D000758:Anesthesia; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000627:therapeutic use; D001640:Bicuculline; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D004597:Electroshock; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010433:Pentylenetetrazole / Q000008:administration & dosage; D010880:Piperidines / Q000138:chemical synthesis* / Q000627:therapeutic use; D011188:Potassium / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000627:therapeutic use; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013329:Structure-Activity Relationship; D014701:Veratridine / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D010880:Piperidines; D011758:Pyrroles; C106267:RWJ 37868; D014701:Veratridine; D011188:Potassium; D002118:Calcium; D010433:Pentylenetetrazole; D001640:Bicuculline