title: Synthesis and structure-activity relationships of pyrazolo[1,5-a]pyridine derivatives: potent and orally active antagonists of corticotropin-releasing factor 1 receptor.
abstract: Design, synthesis, and structure-activity relationships of a series of 3-dialkylamino-7-phenyl pyrazolo[1,5-a]pyridines (I) as selective antagonists of the corticotropin-releasing factor 1 (CRF(1)) receptor are described. The most prominent compound to emerge from this work, 46 (E2508), exhibits potent in vitro activity, excellent drug-like properties, and robust oral efficacy in animal models of stress-related disorders. It has advanced into clinical trials.
authors.affiliation: Medicinal Chemistry, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan. y4-takahashi@hhc.eisai.co.jp
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Shigeki
authors.initials: S
authors.lastname: Hibi
authors.forename: Yorihisa
authors.initials: Y
authors.lastname: Hoshino
authors.forename: Koichi
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Kogyoku
authors.initials: K
authors.lastname: Shin
authors.forename: Kaoru
authors.initials: K
authors.lastname: Murata-Tai
authors.forename: Masae
authors.initials: M
authors.lastname: Fujisawa
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Ino
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shibata
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yonaga
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D000242:Cyclic AMP / Q000096:biosynthesis; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
chemical_list: D000928:Antidepressive Agents; D011720:Pyrazoles; D011725:Pyridines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000242:Cyclic AMP; C575281:N-(cyclopropylmethyl)-7-(2,6-dimethoxy-4-(methoxymethyl)phenyl)-2-ethyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo(1,5-a)pyridin-3-amine