title: Cyanoamidines. II. Synthesis and pharmacological activity of N-arylalkyl-N'-cyano-3-pyridinecarboxamidines.
abstract: A new series of cyanoamidines, N-arylalkyl-N'-cyano-3-pyridinecarboxamidines was synthesized and evaluated for inhibitory effects on 40 mM KCl-induced contraction and norepinephrine (NE)-induced contraction of rat aorta strips. The N-phenethyl cyanoamidine 4c showed potent vasodilatory action. Further in vitro screening program using 4c as a lead compound resulted in the discovery of highly potent N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine (5j). Compound 5j induced the greatest increase in 86Rb+ efflux among cyanoamidine series. Subsequent modification of the pyridine ring of 5j was performed with evaluation for intravenous and oral antihypertensive activities. Introduction of an amino group at the 5-position of the pyridine ring furnished the new potassium channel opener, 5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine+ ++ (9e; KRN4884), which showed highly potent antihypertensive activity and a long duration of antihypertensive action after oral administration. KRN4884 is under further development as an antihypertensive agent.
authors.affiliation: Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakajima
authors.forename: S
authors.initials: S
authors.lastname: Nakajima
authors.forename: T
authors.initials: T
authors.lastname: Izawa
authors.forename: T
authors.initials: T
authors.lastname: Kashiwabara
authors.forename: Y
authors.initials: Y
authors.lastname: Munezuka
mesh_terms: D000284:Administration, Oral; D000578:Amidines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D012414:Rubidium Radioisotopes; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000578:Amidines; D000959:Antihypertensive Agents; D011725:Pyridines; D012414:Rubidium Radioisotopes; D014665:Vasodilator Agents; D009638:Norepinephrine