title: Synthesis, characterization, and biological assessment of the four stereoisomers of the H(3) receptor antagonist 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl)phenyl]benzamide.
abstract: This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl) phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a-8d were determined. Stereoisomer 8c (2S,3'S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities.
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: Raisa
authors.initials: R
authors.lastname: Nagorny
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Pruniaux
authors.forename: James A
authors.initials: JA
authors.lastname: Hendrix
authors.forename: Pascal G
authors.initials: PG
authors.lastname: George
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism; D006207:Half-Life; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: C585739:5-fluoro-2-methyl-N-(2-methyl-4-(2-methyl(1,3')bipyrrolidinyl-1'-yl)phenyl)benzamide; D001549:Benzamides; D006633:Histamine Antagonists; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; C037689:benzamide