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: J R Carson, R J Carmosin, P M Pitis, J L Vaught, H R Almond, J P Stables, H H Wolf, E A Swinyard, H S White
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 40 Issue 11 Pg. 1578-84 (May 23 1997) ISSN: 0022-2623 [Print] United States
• PMID: 9171868 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anticonvulsants
• Piperidines
• Pyrroles
• RWJ 37868
• Veratridine
• Potassium
• Calcium
• Pentylenetetrazole
• Bicuculline

Topics

• Anesthesia
• Animals
• Anticonvulsants (chemical synthesis, therapeutic use)
• Bicuculline
• Calcium (metabolism)
• Cerebellum (drug effects, metabolism)
• Electroshock
• Mice
• Models, Molecular
• Molecular Structure
• Pentylenetetrazole (administration & dosage)
• Piperidines (chemical synthesis, therapeutic use)
• Potassium (pharmacology)
• Pyrroles (chemical synthesis, therapeutic use)
• Rats
• Seizures (chemically induced, prevention & control)
• Structure-Activity Relationship
• Veratridine (pharmacology)