Discovery of new diphenyloxazole derivatives containing a pyrrolidine ring: orally active prostacyclin mimetics. Part 2.
Synthetic and biological evaluation of novel diphenyloxazole derivatives containing a pyrrolidine ring, as a prostacyclin mimetic without the PG skeleton, are described. Asymmetric reduction of a ketone using a chiral Ru complex and reductive amination by NaBH(4) produces four isomers of the tetrahydronaphthalene ring and the pyrrolidine ring with high stereoselectivity. FR193262 (4), (R,R)-diphenyloxazolyl pyrrolidine derivative, displays high potency and agonist efficacy at the IP receptor and has good bioavailability in rats and dogs.
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
Okitsu
Osamu
O
Tabuchi
Seiichiro
S
Taniguchi
Kiyoshi
K
Nishio
Mie
M
Koyama
Satoshi
S
Seki
Jiro
J
Sakane
Kazuo
K
D000818:Animals; D001682:Biological Availability; D004285:Dogs; D011464:Epoprostenol / Q000037:antagonists & inhibitors*; D000882:Haplorhini; D006801:Humans; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011759:Pyrrolidines; D051381:Rats; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D019163:Reducing Agents; D013045:Species Specificity; D013329:Structure-Activity Relationship
D010080:Oxazoles; C113936:PTGIR protein, human; D011759:Pyrrolidines; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D019163:Reducing Agents; D011464:Epoprostenol; C032519:pyrrolidine