Design and synthesis of ether analogues as potent and selective M2 muscarinic receptor antagonists.
Novel, selective M2 muscarinic antagonists, which replace the metabolically labile styrenyl moiety of the prototypical M2 antagonist 1 with an ether linkage, were synthesized. A detailed SAR study in this class of compounds has yielded highly active compounds that showed M2 Ki values of < 1.0 nM and >100-fold selectivity against M1, M3, and M5 receptors.
Wang
Y
Y
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. yuguang.wang@spcorp.com
Chackalamannil
S
S
Chang
W
W
Greenlee
W
W
Ruperto
V
V
Duffy
R A
RA
McQuade
R
R
Lachowicz
J E
JE
D000109:Acetylcholine / Q000819:agonists*; D000475:Alkenes / Q000138:chemical synthesis; D015195:Drug Design; D004986:Ether / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D018727:Muscarinic Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D043642:Receptor, Muscarinic M5; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000475:Alkenes; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D043642:Receptor, Muscarinic M5; D011976:Receptors, Muscarinic; D004986:Ether; D000109:Acetylcholine