title: Synthesis and histamine H2-receptor antagonist activity of 4-(1-pyrazolyl)butanamides, guanidinopyrazoles, and related compounds.
abstract: A series of 4-(1-pyrazolyl)butanamides, pyrazolylalkyl cyanoguanidines, and related compounds with diverse functional groups (e.g. nitro, amino, guanidino groups) in the 3-position of the pyrazole ring was prepared via 4-(3-nitro-1-pyrazolyl)butanenitrile (5) and the corresponding carboxylic acid 7 as central intermediates. The amides 9a-d were prepared from the primary amines 8a-d which represent partial structures of the H2-receptor antagonists roxatidine, cimetidine, ranitidine, and famotidine. The roxatidine-derived 4-(3-nitro-1-pyrazolyl)butanamide (9a) proved to be the compound with the highest H2-receptor antagonist activity of 23 compounds tested at the isolated guinea pig right atrium preparation, achieving about 6 times famotidine's or 160 times cimetidine's potency. By contrast, in Ghosh-Schild rats 9a did not inhibit histamine-stimulated gastric acid secretion at a dosage of 0.1 mumol/kg i.v. Compounds 20a (the 3-(trifluoroethyl-guanidino)pyrazole analogue of 9a, 12a (the cyanoguanidine analogue) and N-(4-[3-(trifluoroethylguanidino)-1-pyrazolyl]butyl)cyanogua nidine (29), which are about as active as famotidine in the atrium, turned out to be very potent inhibitors of gastric acid secretion as well (e.g., 29: 74% inhibition at 0.025 mumol/kg). These compounds are comparable to famotidine in the rat stomach and by far superior to cimetidine and ranitidine in this test system.
authors.affiliation: Institute of Pharmacy, University of Regensburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Buschauer
authors.forename: R
authors.initials: R
authors.lastname: Mohr
authors.forename: W
authors.initials: W
authors.lastname: Schunack
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D005744:Gastric Acid / Q000378:metabolism; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000577:Amides; D006146:Guanidines; D006635:Histamine H2 Antagonists; D011720:Pyrazoles