Meta-substituted benzofused macrocyclic lactams as zinc metalloprotease inhibitors.
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.
Ksander
G M
GM
Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901, USA.
de Jesus
R
R
Yuan
A
A
Ghai
R D
RD
McMartin
C
C
Bohacek
R
R
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011487:Protein Conformation; D012984:Software; D013698:Templates, Genetic
D000806:Angiotensin-Converting Enzyme Inhibitors; D007769:Lactams; D015260:Neprilysin