Metabolism investigation leading to novel drug design: orally active prostacyclin mimetics. Part 4.
A metabolism study of FR181157 (1) led to the discovery of new oxazole derivatives as active metabolites. The metabolite 6 with an epoxy ring exhibited high anti-aggregative potency with an IC(50) of 5.8 nM and potent binding affinity for the human recombinant IP receptor with a K(i) value of 6.1 nM and selectivity for human IP receptor over all other members of the human prostanoid receptor family.
Hattori
Kouji
K
Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. kouji_hattori@po.fujisawa.co.jp
Takamura
Fujiko
F
Tanaka
Akira
A
Takasugi
Hisashi
H
Taniguchi
Kiyoshi
K
Nishio
Mie
M
Koyama
Satoshi
S
Seki
Jiro
J
Sakane
Kazuo
K
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D015195:Drug Design; D011464:Epoprostenol / Q000819:agonists / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000378:metabolism; D018716:Molecular Mimicry; D010080:Oxazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D010599:Pharmacokinetics; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D010080:Oxazoles; C113936:PTGIR protein, human; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D011464:Epoprostenol