Improving the Oral Efficacy of CNS Drug Candidates:  Discovery of Highly Orally Efficacious Piperidinyl Piperidine M2 Muscarinic Receptor Antagonists

In search of a backup M2 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 comp...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2002-12, Vol.45 (25), p.5415-5418
Main Authors: Wang, Yuguang, Chackalamannil, Samuel, Hu, Zhiyong, Greenlee, William J, Clader, John, Boyle, Craig D, Kaminski, James J, Billard, William, Binch, Crosby, Gordon, Ruperto, Vilma, Duffy, Ruth A, Cohen-Williams, Mary, Coffin, Vicki L, Cox, Kathleen A, Grotz, Diane E, Lachowicz, Jean E
Format: Article
Language:English
Subjects:
Acetylcholine - metabolism
Administration, Oral
Animals
Autoreceptors - antagonists & inhibitors
Avoidance Learning - drug effects
Biological and medical sciences
Central Nervous System Agents - chemical synthesis
Central Nervous System Agents - chemistry
Central Nervous System Agents - pharmacology
Cholinergic system
Corpus Striatum - metabolism
Humans
In Vitro Techniques
Medical sciences
Microdialysis
Molecular Conformation
Muscarinic Antagonists - chemical synthesis
Muscarinic Antagonists - chemistry
Muscarinic Antagonists - pharmacology
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Piperidines - chemical synthesis
Piperidines - chemistry
Piperidines - pharmacology
Rats
Receptor, Muscarinic M2
Receptors, Muscarinic - drug effects
Structure-Activity Relationship
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Description
Summary:In search of a backup M2 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0255163