title: Design and synthesis of a novel series of histamine H3 receptor antagonists through a scaffold hopping strategy.
abstract: Lead compounds 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-benzamide (1), tetrahydro-pyran-4-carboxylic acid [((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-amide (2), and 3,5-dimethyl-isoxazole-4-carboxylic acid [((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-amide (3) discovered in our laboratory, displayed high histamine H3 receptor (H3R) affinity, good selectivity and weak human Ether-à-go-go-Related Gene (hERG) channel affinity with desirable overall physico-chemical and pharmacokinetic (PK) profiles. Herein, we describe the design and synthesis of a novel series of H3R antagonists utilizing a scaffold hopping strategy. Further structure-activity relationship (SAR) studies of the series culminated in the identification of ((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-naphthalene-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide (4c) and -[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-N-(tetrahydro-pyran-4-yl)-acetamide (4d), which exhibited good H3R affinity in vitro, good selectivity, and desirable PK properties. Compounds 4c and 4d were also assessed in cardiac safety experiments. In particular, the effects of the compounds on action potentials recorded from ventricular myocytes isolated from guinea pigs were used to screen compounds that not only displayed a low affinity towards hERG channel, but also had lower interference with other cardiac ion channels. Compound 4c did not alter the major parameters in this model system at ⩽10 μM, and no significant induction of any major haemodynamic effect when intravenously administered at 3mg/kg dose to anaesthetized mongrel dogs. Compound 4c is a new promising lead as orally potent and selective H3R antagonist belonging to a distinct structural class.
authors.affiliation: LGCR SMRPD Chemical Research, Sanofi US, 153-1-130, 153 2nd Ave, Waltham, MA 02451, USA. Electronic address: zhongli.gao@sanofi.com.
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Sanofi US, 55C-420A, 55 Corporate Drive, Bridgewater, NJ 08807, USA. Electronic address: william.hurst@sanofi.com.
authors.forename: William J
authors.initials: WJ
authors.lastname: Hurst
authors.affiliation: Sanofi US, 55C-420A, 55 Corporate Drive, Bridgewater, NJ 08807, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hall
authors.affiliation: Sanofi US, 55C-420A, 55 Corporate Drive, Bridgewater, NJ 08807, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Hartung
authors.affiliation: Sanofi US, 55C-420A, 55 Corporate Drive, Bridgewater, NJ 08807, USA.
authors.forename: William
authors.initials: W
authors.lastname: Reynolds
authors.affiliation: Proteogenomics, Sanofi/Genzyme R&D Center, 49 New York Avenue, Framingham, MA 01701, USA.
authors.forename: Jiesheng
authors.initials: J
authors.lastname: Kang
authors.affiliation: Sanofi US, 55C-420A, 55 Corporate Drive, Bridgewater, NJ 08807, USA.
authors.forename: Raisa
authors.initials: R
authors.lastname: Nagorny
authors.affiliation: Sanofi US, 55C-420A, 55 Corporate Drive, Bridgewater, NJ 08807, USA. Electronic address: jhendrix@alz.org.
authors.forename: James A
authors.initials: JA
authors.lastname: Hendrix
authors.affiliation: Sanofi R&D, 1, Avenue Pierre Brossolette, Chilly-Mazarin 91385, France.
authors.forename: Pascal G
authors.initials: PG
authors.lastname: George
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004285:Dogs; D015195:Drug Design; D005260:Female; D006168:Guinea Pigs; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008297:Male; D018408:Patch-Clamp Techniques; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism; D000071230:Transcriptional Regulator ERG
chemical_list: C072312:ERG protein, human; D054828:Histamine H3 Antagonists; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
keywords: Cardiac myocyte model; Histamine H(3) receptor antagonist/inverse agonist; Scaffold hopping; Structure activity relationship