title: Metabolic stabilization of benzylidene ketal M(2) muscarinic receptor antagonists via halonaphthoic acid substitution.
abstract: The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. craig.boyle@spcorp.com
authors.forename: C D
authors.initials: CD
authors.lastname: Boyle
authors.forename: S
authors.initials: S
authors.lastname: Chackalamannil
authors.forename: J W
authors.initials: JW
authors.lastname: Clader
authors.forename: W J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: H B
authors.initials: HB
authors.lastname: Josien
authors.forename: J J
authors.initials: JJ
authors.lastname: Kaminski
authors.forename: J A
authors.initials: JA
authors.lastname: Kozlowski
authors.forename: S W
authors.initials: SW
authors.lastname: McCombie
authors.forename: D V
authors.initials: DV
authors.lastname: Nazareno
authors.forename: J R
authors.initials: JR
authors.lastname: Tagat
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: G
authors.initials: G
authors.lastname: Zhou
authors.forename: W
authors.initials: W
authors.lastname: Billard
authors.forename: H
authors.initials: H
authors.lastname: Binch
authors.forename: G
authors.initials: G
authors.lastname: Crosby
authors.forename: M
authors.initials: M
authors.lastname: Cohen-Williams
authors.forename: V L
authors.initials: VL
authors.lastname: Coffin
authors.forename: K A
authors.initials: KA
authors.lastname: Cox
authors.forename: D E
authors.initials: DE
authors.lastname: Grotz
authors.forename: R A
authors.initials: RA
authors.lastname: Duffy
authors.forename: V
authors.initials: V
authors.lastname: Ruperto
authors.forename: J E
authors.initials: JE
authors.lastname: Lachowicz
mesh_terms: D000109:Acetylcholine / Q000032:analysis / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001597:Benzylidene Compounds / Q000737:chemistry* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004149:Dioxoles / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D006801:Humans; D008252:Macaca fascicularis; D017551:Microdialysis; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C442374:1-((3,4-methylenedioxyphenyl)sulfonylphenyl)-1-(1-(1-(n-propylsulfonyl)morpholin-4-yl)morpholin-4-yl)dioxole; C442375:1-((4-methoxyphenyl)sulfonylphenyl)-1(1-(1-(1-naphthylcarbonyl)morpholin-4-yl)morpholin-4-yl)dioxole; C442376:1-((4-methoxyphenyl)sulfonylphenyl)-1-(1-(1-(4-fluoro-1-naphthylcarbonyl)morpholin-4-yl)morpholin-4-yl)dioxole; D001597:Benzylidene Compounds; D004149:Dioxoles; D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D013450:Sulfones; D003577:Cytochrome P-450 Enzyme System; D000109:Acetylcholine