| Autor: |
Ksander GM; Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901, USA., de Jesus R, Yuan A, Ghai RD, McMartin C, Bohacek R |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 1997 Feb 14; Vol. 40 (4), pp. 506-14. |
| DOI: |
10.1021/jm960583g |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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