Improving the oral efficacy of CNS drug candidates: discovery of highly orally efficacious piperidinyl piperidine M2 muscarinic receptor antagonists.
In search of a backup M(2) muscarinic receptor antagonist to the previously reported compound 1, we discovered compound (+)-14, which showed superior oral efficacy in animal models. The improvement of oral efficacy was achieved by modulating both the molecular weight and lipophilicity of the lead compounds.
Wang
Yuguang
Y
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. yuguang.wang@spcorp.com
Chackalamannil
Samuel
S
Hu
Zhiyong
Z
Greenlee
William J
WJ
Clader
John
J
Boyle
Craig D
CD
Kaminski
James J
JJ
Billard
William
W
Binch
Herbert
H
Crosby
Gordon
G
Ruperto
Vilma
V
Duffy
Ruth A
RA
Cohen-Williams
Mary
M
Coffin
Vicki L
VL
Cox
Kathleen A
KA
Grotz
Diane E
DE
Lachowicz
Jean E
JE
D000109:Acetylcholine / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D017660:Autoreceptors / Q000037:antagonists & inhibitors*; D001362:Avoidance Learning / Q000187:drug effects; D002491:Central Nervous System Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D017551:Microdialysis; D008968:Molecular Conformation; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013329:Structure-Activity Relationship
D017660:Autoreceptors; D002491:Central Nervous System Agents; D018727:Muscarinic Antagonists; D010880:Piperidines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D000109:Acetylcholine