Metabolic stabilization of benzylidene ketal M-2 muscarinic receptor antagonists via halonaphthoic acid substitution

Authors
Boyle, CD Chackalamannil, S Clader, JW Greenlee, WJ Josien, HB Kaminski, JJ Kozlowski, JA McCombie, SW Nazareno, DV Tagat, JR Wang, YG Zhou, GW Billard, W Binch, H Crosby, G Cohen-Williams, M Coffin, VL Cox, KA Grotz, DE Duffy, RA Ruperto, V Lachowicz, JE
Citation
Cd. Boyle et al., Metabolic stabilization of benzylidene ketal M-2 muscarinic receptor antagonists via halonaphthoic acid substitution, BIOORG MED, 11(17), 2001, pp. 2311-2314
Citations number
26
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
ISSN journal
0960894X → ACNP
Volume
11
Issue
17
Year of publication
2001
Pages
2311 - 2314
Database
ISI
SICI code
0960-894X(20010903)11:17<2311:MSOBKM>2.0.ZU;2-U
Abstract
The potential toxicological liabilities of the M-2 muscarinic antagonist I were addressed by replacing the methylenedioxyphenyl moiety with a p-methox yphenyl group, resulting in M-2 selective compounds such as 3. Several halo genated naphthamide derivatives of 3 were studied in order to improve the p harmacokinetic profile via blockage of oxidative metabolism. Compound 4 dem onstrated excellent M2 affinity and selectivity, human microsomal stability , and oral bioavailability in rodents and primates. (C) 2001 Elsevier Scien ce Ltd. All rights reserved.