title: Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part II).
abstract: A novel series of histamine H3 receptor (H3R) antagonists was derived from an arylurea lead series (1) via bioisosteric replacement of the urea functionality by an amide linkage. The arylamide series was optimized through SAR studies by a broad variation of substituents in the left-hand side benzoyl residue (analogs 2a-2ag) or replacement of the benzoyl moiety by heteroarylcarbonyl residues (analogs 5a-5n). Compounds 2p and 2q were identified within the series as potent and selective H3R antagonists/inverse agonists with acceptable overall profile. Compound 2q was orally active in food intake inhibition in diet-induced obese (DIO) mice. Compound 2q represents a novel H3R antagonist template with improved in vitro potency and oral efficacy and has its merits as a new lead for further optimization.
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: D000284:Administration, Oral; D000577:Amides / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D018938:Caco-2 Cells; D004353:Drug Evaluation, Preclinical; D054314:Drug Inverse Agonism; D054828:Histamine H3 Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy; D011485:Protein Binding; D011759:Pyrrolidines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; 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; D001549:Benzamides; D054828:Histamine H3 Antagonists; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; D014508:Urea