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Hydroxyimine NO-donors; FK409 and derivatives
1Planning & Administration, Development, Astellas Pharma Inc., Itabashi-ku, Tokyo, Japan. keizo.yoshida@jp.astellas.com
Current Topics in Medicinal Chemistry
|August 17, 2005
Summary
FK409, a potent vasodilator, showed efficacy for angina but caused anemia. Development was halted due to this adverse effect, leading to research into safer alternatives like FR144220 and FR146881.
Area of Science:
- Cardiovascular Pharmacology
- Medicinal Chemistry
Background:
- FK409, a semisynthetic compound, emerged from microbial screening for prostaglandin-like compounds.
- It exhibits potent vasodilation, similar to organic nitrates like nitroglycerin (NTG).
Purpose of the Study:
- To evaluate FK409's efficacy and safety in treating angina pectoris.
- To explore chemically stable derivatives with improved pharmacokinetic profiles and reduced anemia risk.
Main Methods:
- In vitro and in vivo studies assessing vasodilation and potency compared to NTG.
- Clinical trials in patients with angina pectoris and ischemic heart disease.
- Development of back-up compounds (FR144220, FR146881) focusing on stability and NO release.
Main Results:
- FK409 demonstrated potent vasodilation, particularly in larger coronary vessels, and efficacy in angina patients (60-70% improvement).
- Anemia was identified as a significant drug-related adverse event in clinical studies.
- Chemically stable derivatives, FR144220 and FR146881, exhibited longer duration of action.
Conclusions:
- FK409 offers comparable efficacy to organic nitrates but is limited by anemia risk.
- Development of FK409 was terminated; focus shifted to derivatives with improved safety and pharmacokinetics.
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