| Title : Metabolic stabilization of benzylidene ketal M(2) muscarinic receptor antagonists via halonaphthoic acid substitution - Boyle_2001_Bioorg.Med.Chem.Lett_11_2311 |
| Author(s) : Boyle CD , Chackalamannil S , Clader JW , Greenlee WJ , Josien HB , Kaminski JJ , Kozlowski JA , McCombie SW , Nazareno DV , Tagat JR , Wang Y , Zhou G , Billard W , Binch H , Crosby G , Cohen-Williams M , Coffin VL , Cox KA , Grotz DE , Duffy RA , Ruperto V , Lachowicz JE |
| Ref : Bioorganic & Medicinal Chemistry Lett , 11 :2311 , 2001 |
|
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. |
| PubMedSearch : Boyle_2001_Bioorg.Med.Chem.Lett_11_2311 |
| PubMedID: 11527721 |
Boyle CD, Chackalamannil S, Clader JW, Greenlee WJ, Josien HB, Kaminski JJ, Kozlowski JA, McCombie SW, Nazareno DV, Tagat JR, Wang Y, Zhou G, Billard W, Binch H, Crosby G, Cohen-Williams M, Coffin VL, Cox KA, Grotz DE, Duffy RA, Ruperto V, Lachowicz JE (2001)
Metabolic stabilization of benzylidene ketal M(2) muscarinic receptor antagonists via halonaphthoic acid substitution
Bioorganic & Medicinal Chemistry Lett
11 :2311
Boyle CD, Chackalamannil S, Clader JW, Greenlee WJ, Josien HB, Kaminski JJ, Kozlowski JA, McCombie SW, Nazareno DV, Tagat JR, Wang Y, Zhou G, Billard W, Binch H, Crosby G, Cohen-Williams M, Coffin VL, Cox KA, Grotz DE, Duffy RA, Ruperto V, Lachowicz JE (2001)
Bioorganic & Medicinal Chemistry Lett
11 :2311