Linked Life Data

9667962

Source:http://linkedlifedata.com/resource/pubmed/id/9667962

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
15
pubmed:dateCreated
1998-8-3
pubmed:abstractText
A series of novel benzimidazoles (BI) derived from the indole 2 was synthesized and evaluated as selective neuropeptide Y (NPY) Y1 receptor antagonists with the aim of developing antiobesity drugs. In our SAR approach, the (4-chlorophenoxy)methyl group at C-2 was kept constant and a series of BIs substituted with various piperidinylalkyl groups at N-1 was synthesized to identify the optimal spacing and orientation of the piperidine ring nitrogen relative to the benzimidazole. The 3-(3-piperidinyl)propyl in 33 was found to maximize affinity for the Y1 receptor. Because of the critical importance of Arg33 and Arg35 of NPY binding to the Y1 receptor, the incorporation of an additional aminoalkyl functionality to the structure of 33 was explored. Methyl substitution was used to probe where substitution on the aromatic ring was best tolerated. In this fashion, the C-4 was chosen for the substitution of the second aminoalkyl functionality. Synthesis of such compounds with a phenoxy tether using the 4-hydroxybenzimidazole 11 was pursued because of their relative ease of synthesis. Functionalization of the hydroxy group of 45 with a series of piperidinylalkyl groups provided the dibasic benzimidazoles 55-62. Among them, BI 56 demonstrated a Ki of 0.0017 microM, which was 400-fold more potent than 33. To evaluate if there was a stereoselective effect on affinity for these BIs, the four constituent stereoisomers (69-72) of the BI 60 were prepared using the S- and R-isomers of bromide 17. Antagonist activity of these BIs was confirmed by measuring the ability of selected compounds to reverse NPY-induced forskolin-stimulated cyclic AMP. The high selectivity of several BI antagonists for the Y1 versus Y2, Y4, and Y5 receptors was also shown.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
16
pubmed:volume
41
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2709-19
pubmed:dateRevised
2004-11-17
pubmed:meshHeading
pubmed:year
1998
pubmed:articleTitle
Synthesis and evaluation of a series of novel 2-[(4-chlorophenoxy)methyl]benzimidazoles as selective neuropeptide Y Y1 receptor antagonists.
pubmed:affiliation
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. Zarrinmayeh_Hamideh@Lilly.Com
pubmed:publicationType
Journal Article