6,7-Dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidines and their derivatives as novel corticotropin-releasing factor 1 receptor antagonists

Tetsuji Saito; Tetsuo Obitsu; Takashi Kondo; Toshiaki Matsui; Yuuki Nagao; Kensuke Kusumi; Naoya Matsumura; Sonoko Ueno; Akihiro Kishi; Seishi Katsumata; Yoshifumi Kagamiishi; Hisao Nakai; Masaaki Toda

doi:10.1016/j.bmc.2011.07.055

6,7-Dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidines and their derivatives as novel corticotropin-releasing factor 1 receptor antagonists

Bioorg Med Chem. 2011 Sep 15;19(18):5432-45. doi: 10.1016/j.bmc.2011.07.055. Epub 2011 Jul 31.

Authors

Tetsuji Saito¹, Tetsuo Obitsu, Takashi Kondo, Toshiaki Matsui, Yuuki Nagao, Kensuke Kusumi, Naoya Matsumura, Sonoko Ueno, Akihiro Kishi, Seishi Katsumata, Yoshifumi Kagamiishi, Hisao Nakai, Masaaki Toda

Affiliation

¹ Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. te.saitou@ono.co.jp

PMID: 21865047
DOI: 10.1016/j.bmc.2011.07.055

Abstract

To identify an orally active corticotropin-releasing factor 1 receptor antagonist, a series of 6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidines and their derivatives were designed, synthesized and evaluated. An in vitro study followed by in vivo and pharmacokinetic studies of these heterotricyclic compounds led us to the discovery of an orally active CRF1 receptor antagonist. The results of a structure-activity relationship study are presented.

MeSH terms

Animals
CHO Cells
Cricetinae
Dose-Response Relationship, Drug
Drug Design
Male
Maze Learning / drug effects
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Rats
Rats, Sprague-Dawley
Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
Stereoisomerism
Structure-Activity Relationship
Swine

Substances

Pyrazoles
Pyrimidines
Receptors, Corticotropin-Releasing Hormone