Discovery of new diphenyloxazole derivatives containing a pyrrolidine ring: orally active prostacyclin mimetics. Part 2

Kouji Hattori; Osamu Okitsu; Seiichiro Tabuchi; Kiyoshi Taniguchi; Mie Nishio; Satoshi Koyama; Jiro Seki; Kazuo Sakane

doi:10.1016/j.bmcl.2005.04.042

Discovery of new diphenyloxazole derivatives containing a pyrrolidine ring: orally active prostacyclin mimetics. Part 2

Bioorg Med Chem Lett. 2005 Jul 1;15(13):3279-83. doi: 10.1016/j.bmcl.2005.04.042.

Authors

Kouji Hattori¹, Osamu Okitsu, Seiichiro Tabuchi, Kiyoshi Taniguchi, Mie Nishio, Satoshi Koyama, Jiro Seki, Kazuo Sakane

Affiliation

¹ Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. kouji_hattori@po.fujisawa.co.jp

PMID: 15935660
DOI: 10.1016/j.bmcl.2005.04.042

Abstract

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.

MeSH terms

Animals
Biological Availability
Dogs
Epoprostenol / antagonists & inhibitors*
Haplorhini
Humans
Inhibitory Concentration 50
Molecular Mimicry
Oxazoles / chemical synthesis*
Oxazoles / pharmacokinetics
Oxazoles / pharmacology
Pyrrolidines
Rats
Receptors, Epoprostenol
Receptors, Prostaglandin / antagonists & inhibitors*
Reducing Agents
Species Specificity
Structure-Activity Relationship

Substances

Oxazoles
PTGIR protein, human
Pyrrolidines
Receptors, Epoprostenol
Receptors, Prostaglandin
Reducing Agents
Epoprostenol
pyrrolidine