title: Identification and profiling of 3,5-dimethyl-isoxazole-4-carboxylic acid [2-methyl-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)phenyl] amide as histamine H(3) receptor antagonist for the treatment of depression.
abstract: Lead optimization guided by histamine H3 receptor (H3R) affinity and calculated physico-chemical properties enabled simultaneous improvement in potency and PK properties leading to the identification of a potent, selective, devoid of hERG issues, orally bioavailable, and CNS penetrable H3R antagonist/inverse agonist 3h. The compound was active in forced-swimming tests suggesting its potential therapeutic utility as an anti-depressive agent. This Letter further includes its cardiovascular and neuropsychological/behavioral safety assessments.
authors.affiliation: LGCR SMRPD Chemical Research, Sanofi US, 153-1-122, 153 2nd Ave, Waltham, MA 02451, USA. Electronic address: zhongli.gao@sanofi.com.
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Gao
authors.forename: William J
authors.initials: WJ
authors.lastname: Hurst
authors.forename: Werngard
authors.initials: W
authors.lastname: Czechtizky
authors.forename: Daniel
authors.initials: D
authors.lastname: Hall
authors.forename: Nicolas
authors.initials: N
authors.lastname: Moindrot
authors.forename: Raisa
authors.initials: R
authors.lastname: Nagorny
authors.forename: Philippe
authors.initials: P
authors.lastname: Pichat
authors.forename: David
authors.initials: D
authors.lastname: Stefany
authors.forename: James A
authors.initials: JA
authors.lastname: Hendrix
authors.forename: Pascal G
authors.initials: PG
authors.lastname: George
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D016466:CHO Cells; D003412:Cricetulus; D006633:Histamine Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000737:chemistry / Q000378:metabolism
chemical_list: D000577:Amides; D000928:Antidepressive Agents; D006633:Histamine Antagonists; D011759:Pyrrolidines; D018100:Receptors, Histamine H3
keywords: Anxiety; Depression; Experimental models of anxiety and depression; Forced swimming test; Histamine H(3) receptor antagonist/inverse agonist