FR144420, a novel, slow, nitric oxide-releasing agent

• Published in: European journal of pharmacology 1995-03, Vol.275 (2), p.125-130
• Main Authors: Kita, Yasuhiro, Ohkubo, Kazumi, Hirasawa, Yoshimi, Katayama, Yoshiki, Ohno, Mitsuko, Nishino, Shigetaka, Kato, Masayuki, Yoshida, Keizo
• Format: Article
• Language: English
• Subjects: Administration, Oral; Analysis of Variance; Animals; Antihypertensive Agents - administration & dosage; Antihypertensive Agents - metabolism; Antihypertensive Agents - pharmacology; Antihypertensive Agents - therapeutic use; Aorta - drug effects; Aorta - metabolism; Biological and medical sciences; Blood Pressure - drug effects; Cardiovascular system; Disease Models, Animal; Drug Stability; FK409; FR144420; Hypertension - drug therapy; In Vitro Techniques; Injections, Intravenous; Male; Medical sciences; Miscellaneous; Muscle Contraction - drug effects; Muscle Relaxation - drug effects; Muscle, Smooth, Vascular - drug effects; Nicotinic Acids - metabolism; Nicotinic Acids - pharmacology; Nicotinic Acids - therapeutic use; Nitric oxide (NO); Nitric Oxide - analysis; Nitric Oxide - metabolism; Nitro Compounds - metabolism; Nitro Compounds - pharmacology; Nitro Compounds - therapeutic use; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Stereoisomerism; Vasodilator Agents - metabolism; Vasodilator Agents - pharmacology; Vasodilator Agents - therapeutic use
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/0014-2999(94)00750-2

We report that (±)-( E)-ethyl-2-[( E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409) decomposes and releases nitric oxide (NO) spontaneously in solution. (±)- N-[(E)-4-Ethyl-3-[( Z)-hydroxyimino]-5-nitro-3-hexen-1-yl]-3-pyridinecarboxamide (FR144420) was synthesized with the aim of discovering a compound with longer duration of effects in vivo, compared with FK409. FR144420, like FK409, released NO spontaneously in solution, but the amount of NO released from FR144420 during a 5-min incubation was half the amount from FK409. In addition, FR144420 spontaneously decomposed and generated nitrite, which is an oxidative metabolite of NO, at half the rate of FK409. In a vasorelaxant study with isolated rat aorta, FR144420 had a weaker potency than FK409 (EC 50 = 54 and 8.1 nM, respectively). In in vivo studies, FR144420 decreased mean blood pressure immediately after intravenous and oral administration to conscious rats. The maximum hypotensive effects of FR144420 were less than those of FK409. However, the durations of FR144420-induced (iv. and p.o.) hypotensive effects were longer than those of FK409-induced effects. In conclusion, FR144420 is more stable and releases NO more slowly in solution than does FK409. In in vivo experiments, FR144420 showed a longer duration of effects than FK409. FR144420 may be very useful for investigating the in vivo actions of NO.