Enhancement of pharmacokinetic properties and in vivo efficacy of benzylidene ketal M(2) muscarinic receptor antagonists via benzamide modification.
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.
Boyle
Craig D
CD
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. craig.boyle@spcorp.com
Vice
Susan F
SF
Campion
Jennifer
J
Chackalamannil
Samuel
S
Lankin
Claire M
CM
McCombie
Stuart W
SW
Billard
William
W
Binch
Herbert
H
Crosby
Gordon
G
Williams
Mary-Cohen
MC
Coffin
Vicki L
VL
Cox
Kathleen A
KA
Grotz
Diane E
DE
Duffy
Ruth A
RA
Ruperto
Vilma
V
Lachowicz
Jean E
JE
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
D001549:Benzamides; D001597:Benzylidene Compounds; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D000109:Acetylcholine