Meta-Substituted Benzofused Macrocyclic Lactams as Zinc Metalloprotease Inhibitors

Abstract

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.

Crystal Structure of Mycobacterium tuberculosis Zinc-dependent Metalloprotease-1 (Zmp1), a Metalloprotease Involved in Pathogenicity

“…The local increased hydrophobicity of Zmp1 compared with the NEP S1 subsite could indicate a higher affinity for inhibitors carrying hydrophobic groups at the P1 site, as observed for ECE-1 (41,42). However, the S1 site leaves the rhamnose moiety of the inhibitor exposed to the solvent and plays a minor role in substrate selectivity, as reported for NEP and ECE-1 (43)(44)(45)(46).…”

Importance and synthesis of benzannulated medium-sized and macrocyclic rings (BMRs)

“…Not surprisingly, therefore, this mild and versatile chemistry has also found some utility for the construction of BMR scaffolds. For example, the bridged benzannulated macrocycle 200 was synthesized starting from amino acid 198 (Scheme 7a) 121 while the benzannulated medium-ring ether (48) was prepared via nucleophilic cleavage of enantiomerically pure 1,2-cyclic sulfamidate 201 with phenol derivative 202, followed by Mitsunobu reaction of 203, which led to the formation of scaffold 204 in 30% overall yield, as shown in Scheme 7b. 122 Another variant of the Mitsunobu reaction was reported to affect the closure of a 13-membered lactone in the presence of supported triphenylphosphine in low yield (10%) but was recently more successful in the formal synthesis of salicylihalamides (206, Scheme 7c).…”

Structure of human Endothelin-converting Enzyme I Complexed with Phosphoramidon

“…This is in agreement with the increased hydrophobicity of the S1 sub-site in ECE-1 and the minor stabilizing role of this sub-site in human NEP, for which both compounds show similar IC 50 values. [42][43][44][45] Extensive studies have shown that there is a clear preference for P1′ residues with large hydrophobic side chains, indicating that the specificity of ECE-1 is essentially ensured by this sub-site. 39 The P1′ residue of phosphoramidon and its interaction with the S1′ sub-site is shown in Fig.…”