title: Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part I).
abstract: A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays.
authors.affiliation: LGCR SMRPD Chemical Research, Sanofi US, 153-1-122, 153 2nd Ave, Waltham, MA 02451, USA. 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: Etienne
authors.initials: E
authors.lastname: Guillot
authors.forename: Werngard
authors.initials: W
authors.lastname: Czechtizky
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lukasczyk
authors.forename: Raisa
authors.initials: R
authors.lastname: Nagorny
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Pruniaux
authors.forename: Lothar
authors.initials: L
authors.lastname: Schwink
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Sanchez
authors.forename: Siegfried
authors.initials: S
authors.lastname: Stengelin
authors.forename: Lei
authors.initials: L
authors.lastname: Tang
authors.forename: Irvin
authors.initials: I
authors.lastname: Winkler
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* / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D054828:Histamine H3 Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D008253:Macaca mulatta; D009765:Obesity / Q000188:drug therapy; D011485:Protein Binding; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D000577:Amides; D054828:Histamine H3 Antagonists; D018100:Receptors, Histamine H3; D014508:Urea