title: Enhancement of pharmacokinetic properties and in vivo efficacy of benzylidene ketal M(2) muscarinic receptor antagonists via benzamide modification.
abstract: We previously reported the initial discovery of a novel class of stabilized benzylidene ketal M(2) receptor antagonists. This paper discusses new analogues consisting of benzamide modifications which not only improved M(2) receptor affinity and selectivity, but also enhanced the pharmacokinetic properties of the series. These changes led to the discovery of a highly potent and selective M(2) antagonist, which demonstrated in vivo efficacy and had good bioavailability in multiple species.
authors.affiliation: Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. craig.boyle@spcorp.com
authors.forename: Craig D
authors.initials: CD
authors.lastname: Boyle
authors.forename: Susan F
authors.initials: SF
authors.lastname: Vice
authors.forename: Jennifer
authors.initials: J
authors.lastname: Campion
authors.forename: Samuel
authors.initials: S
authors.lastname: Chackalamannil
authors.forename: Claire M
authors.initials: CM
authors.lastname: Lankin
authors.forename: Stuart W
authors.initials: SW
authors.lastname: McCombie
authors.forename: William
authors.initials: W
authors.lastname: Billard
authors.forename: Herbert
authors.initials: H
authors.lastname: Binch
authors.forename: Gordon
authors.initials: G
authors.lastname: Crosby
authors.forename: Mary-Cohen
authors.initials: MC
authors.lastname: Williams
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Coffin
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Cox
authors.forename: Diane E
authors.initials: DE
authors.lastname: Grotz
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Duffy
authors.forename: Vilma
authors.initials: V
authors.lastname: Ruperto
authors.forename: Jean E
authors.initials: JE
authors.lastname: Lachowicz
mesh_terms: D000109:Acetylcholine / Q000032:analysis / Q000096:biosynthesis; D000818:Animals; D019540:Area Under Curve; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000737:chemistry* / Q000493:pharmacokinetics*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D017551:Microdialysis; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D001597:Benzylidene Compounds; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D000109:Acetylcholine