Discovery of a new class of potent, selective, and orally active prostaglandin D2 receptor antagonists.
The process of discovering a series of N-(p-alkoxy)benzoyl-2-methylindole-4-acetic acid analogs is presented since these compounds represent a new class of potent, selective, and orally active prostaglandin D2 (PGD2) receptor antagonists. Most of these compounds exhibit strong PGD2 receptor binding and PGD2 receptor antagonism in cAMP formation assays. When given orally, these new antagonists dramatically suppress allergic inflammatory responses, such as the PGD2-induced or OVA-induced increase of vascular permeability. Structure-activity relationship (SAR) data are also discussed.
Torisu
Kazuhiko
K
Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan. torisu@ono.co.jp
Kobayashi
Kaoru
K
Iwahashi
Maki
M
Nakai
Yoshihiko
Y
Onoda
Takahiro
T
Nagase
Toshihiko
T
Sugimoto
Isamu
I
Okada
Yutaka
Y
Matsumoto
Ryoji
R
Nanbu
Fumio
F
Ohuchida
Shuichi
S
Nakai
Hisao
H
Toda
Masaaki
M
D000284:Administration, Oral; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D007210:Indoleacetic Acids / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018926:Anti-Allergic Agents; D007210:Indoleacetic Acids; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor