Discovery of diphenylcarbamate derivatives as highly potent and selective IP receptor agonists: orally active prostacyclin mimetics. Part 3.
The new classes of diphenylcarbamate derivatives with a tetrahydronaphthalene skeleton as highly potent and selective IP agonists have been discovered. The optimized diphenylcarbamate type compound FK-788: (R)-4 exhibited potent antiaggregative potency with an IC50 of 18 nM and high binding affinity for the human recombinant IP receptor with K(i) values of 20 nM and selectivity for human IP over all other members of the human prostanoid receptor family. Compound (R)-4 was shown to exhibit good pharmacokinetic properties in rats and dogs, and also good bioavailability in healthy volunteers.
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
Tanaka
Akira
A
Okitsu
Osamu
O
Tabuchi
Seiichiro
S
Taniguchi
Kiyoshi
K
Nishio
Mie
M
Koyama
Satoshi
S
Higaki
Masahide
M
Seki
Jiro
J
Sakane
Kazuo
K
D000284:Administration, Oral; D000818:Animals; D002219:Carbamates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004285:Dogs; D011464:Epoprostenol / Q000378:metabolism*; D006801:Humans; D018716:Molecular Mimicry; D010974:Platelet Aggregation / Q000187:drug effects*; D019859:Proto-Oncogene Proteins c-met / Q000097:blood; D051381:Rats; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000819:agonists*; D011994:Recombinant Proteins / Q000819:agonists; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D002219:Carbamates; C503755:FK-788; C113936:PTGIR protein, human; C491909:Ptgir protein, rat; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D011994:Recombinant Proteins; D011464:Epoprostenol; D019859:Proto-Oncogene Proteins c-met