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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
4
|
| pubmed:dateCreated |
1997-3-26
|
| pubmed:abstractText |
The design, synthesis, and biochemical profile of meta-substituted benzofused macrocyclic lactams are described. The meta-substituted benzofused macrocyclic lactams were designed to have a degree of flexibility allowing the amide bond to occupy two completely different conformations while maintaining sufficient rigidity to allow for strong interaction between enzyme and inhibitor. Using TFIT, a novel molecular superimposition program, it was shown that the meta analogs could be readily superimposed onto our ACE inhibitor template whereas no low-energy superimpositions of the ortho-substituted macrocycles could be found. The macrocycles were prepared by tethering aldehyde 1 derived from S-glutamic acid or S-aspartic acid to a meta-substituted phosphonium bromide 2. Homologation to a monocarboxylic acid methyl ester malonate followed by deprotection and cyclization gave the macrocyclic frame. Further manipulation gave the desired compounds. Unlike the ortho-substituted benzofused macrocyclic lactams described in the previous paper which are selective NEP inhibitors, the meta-substituted compounds are dual inhibitors of both NEP and ACE. The most potent member of this new series, compound 16a, inhibited both enzymes with an IC50 = 8 nM in NEP and 4 nM in ACE.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Feb
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
14
|
| pubmed:volume |
40
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
506-14
|
| pubmed:dateRevised |
2002-11-1
|
| pubmed:meshHeading |
pubmed-meshheading:9046341-Angiotensin-Converting Enzyme Inhibitors,
pubmed-meshheading:9046341-Crystallography, X-Ray,
pubmed-meshheading:9046341-Drug Design,
pubmed-meshheading:9046341-Lactams,
pubmed-meshheading:9046341-Models, Molecular,
pubmed-meshheading:9046341-Neprilysin,
pubmed-meshheading:9046341-Protein Conformation,
pubmed-meshheading:9046341-Software,
pubmed-meshheading:9046341-Templates, Genetic
|
| pubmed:year |
1997
|
| pubmed:articleTitle |
Meta-substituted benzofused macrocyclic lactams as zinc metalloprotease inhibitors.
|
| pubmed:affiliation |
Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901, USA.
|
| pubmed:publicationType |
Journal Article
|