Linked Life Data

11150173

Source:http://linkedlifedata.com/resource/pubmed/id/11150173

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
26
pubmed:dateCreated
2001-1-18
pubmed:abstractText
A novel series of (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides was designed and synthesized based on the structure and biological profiles of an active metabolite 2 of our prototype muscarinic M(3) receptor selective antagonist 1, to develop a potent, long-acting, orally active M(3) antagonist for the treatment of urinary tract disorders, irritable bowel syndrome, and respiratory disorders. Investigation of (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides containing a phenyl or heterocyclic ring as the piperidinyl side chain in place of the 4-methyl-3-pentenyl moiety of 15a revealed that this acid moiety was a versatile template for improving the selectivity for M(3) over M(2) receptors in comparison with the corresponding cyclopentylphenylacetic acid group. However, since the in vitro metabolic stability of these analogues was insufficient compared with that of 2, further derivatization was performed by introducing an appropriate hydrophilic group into the phenyl or 2-pyridyl ring. Thus, the 1-(6-aminopyridin-2-ylmethyl)piperidine analogue 15y exhibiting 190-fold selectivity for M(3) receptors (K(i) = 2.8 nM) over M(2) receptors (K(i) = 530 nM) in a human binding assay and good in vitro metabolic stability in dog and human hepatic microsomes was identified. This compound has excellent oral activity at 4 h after oral dosing (1 mg/kg), inhibiting methacholine-induced bronchoconstriction in dogs, and may be useful in clinical situations in which M(3) over M(2) selectivity is desirable.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
28
pubmed:volume
43
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5017-29
pubmed:dateRevised
2005-11-17
pubmed:meshHeading
pubmed-meshheading:11150173-Acetamides, pubmed-meshheading:11150173-Acetanilides, pubmed-meshheading:11150173-Administration, Oral, pubmed-meshheading:11150173-Animals, pubmed-meshheading:11150173-Bronchoconstriction, pubmed-meshheading:11150173-Bronchodilator Agents, pubmed-meshheading:11150173-CHO Cells, pubmed-meshheading:11150173-Cricetinae, pubmed-meshheading:11150173-Dogs, pubmed-meshheading:11150173-Drug Stability, pubmed-meshheading:11150173-Humans, pubmed-meshheading:11150173-Microsomes, Liver, pubmed-meshheading:11150173-Muscarinic Antagonists, pubmed-meshheading:11150173-Piperidines, pubmed-meshheading:11150173-Receptor, Muscarinic M2, pubmed-meshheading:11150173-Receptor, Muscarinic M3, pubmed-meshheading:11150173-Receptors, Muscarinic, pubmed-meshheading:11150173-Structure-Activity Relationship, pubmed-meshheading:11150173-Transfection
pubmed:year
2000
pubmed:articleTitle
A potent, long-acting, orally active (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide: novel muscarinic M(3) receptor antagonist with high selectivity for M(3) over M(2) receptors.
pubmed:affiliation
Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan.
pubmed:publicationType
Journal Article