title: Discovery of diphenylcarbamate derivatives as highly potent and selective IP receptor agonists: orally active prostacyclin mimetics. Part 3.
abstract: 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.
authors.affiliation: Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. kouji_hattori@po.fujisawa.co.jp
authors.forename: Kouji
authors.initials: K
authors.lastname: Hattori
authors.forename: Akira
authors.initials: A
authors.lastname: Tanaka
authors.forename: Osamu
authors.initials: O
authors.lastname: Okitsu
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Tabuchi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Mie
authors.initials: M
authors.lastname: Nishio
authors.forename: Satoshi
authors.initials: S
authors.lastname: Koyama
authors.forename: Masahide
authors.initials: M
authors.lastname: Higaki
authors.forename: Jiro
authors.initials: J
authors.lastname: Seki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sakane
mesh_terms: 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
chemical_list: 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