Hydroxyimine NO-donors; FK409 and derivatives.
FK409 was discovered during a screening program for prostaglandin like compounds from microbial products by measuring inhibition of platelet aggregation and vasodilation. FK409, a semisynthetic compound derived from acidic nitrosation of microbial broth, was shown to be a potent vasodilator with a similar pharmacological profile to organic nitrates such as nitroglycerin (NTG). FK409 dilated the larger diameter coronary vascular vessels more potently than those with a smaller diameter in vitro, and was more potent than NTG in a dog angina pectoris model. Clinical development of FK409 for angina pectoris included a preliminary open efficacy study in about twenty patients with angina pectoris showing an improvement in 60-70 % of patients. Anemia proved a drug related adverse event. A new study was carried out on around 20 patients with ischemic heart disease, but in the longer term the anemia remained. It was concluded that FK409 had a comparable efficacy to organic nitrates, but an undesirable adverse effect, and development was terminated. Back-up compounds for FK409, explored improvement of the pharmacokinetic profile: an increase in duration of action and a reduction of the risk of anemia. The pharmacological action of FK409 was associated with increased cGMP levels in aortic smooth muscle; and release of NO was observed by physicochemical methods. Synthesis of chemically more stable derivatives of FK409 with slower NO release was aimed at longer pharmacokinetic profiles and a lower incidence of anemia. FR144220 and FR146881 were identified as chemically more stable compounds with a longer duration of pharmacological action.
Yoshida
Keizo
K
Planning & Administration, Development, Astellas Pharma Inc., Itabashi-ku, Tokyo, Japan. keizo.yoshida@jp.astellas.com
Kita
Yasuhiro
Y
D000740:Anemia / Q000517:prevention & control; D000787:Angina Pectoris / Q000517:prevention & control; D000818:Animals; D002986:Clinical Trials as Topic; D004285:Dogs; D006801:Humans; D007097:Imines / Q000737:chemistry*; D009569:Nitric Oxide / Q000096:biosynthesis; D020030:Nitric Oxide Donors / Q000737:chemistry* / Q000494:pharmacology; D009574:Nitro Compounds / Q000737:chemistry* / Q000494:pharmacology; D016377:Organ Transplantation; D015427:Reperfusion Injury / Q000517:prevention & control; D014665:Vasodilator Agents / Q000737:chemistry* / Q000494:pharmacology
D007097:Imines; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D014665:Vasodilator Agents; D009569:Nitric Oxide; C061872:FK 409