|
|||||
|
|
Metabolic stabilization of benzylidene ketal M(2) muscarinic receptor antagonists via halonaphthoic acid substitution |
|
| Authors: | Boyle C D Chackalamannil S Clader J W Greenlee W J Josien H B Kaminski J J Kozlowski J A McCombie S W Nazareno D V Tagat J R Wang Y Zhou G Billard W Binch H Crosby G Cohen-Williams M Coffin V L Cox K A Grotz D E Duffy R A Ruperto V Lachowicz J E |
| Institution: | Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. craig.boyle@spcorp.com |
| 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. |
| Keywords: | |
| 本文献已被 ScienceDirect PubMed 等数据库收录！ | |