Ortho-Substituted Benzofused Macrocyclic Lactams as Zinc Metalloprotease Inhibitors

Abstract

The design and preparation of ortho-substituted benzofused macrocyclic lactams are described. The benzofused macrocyclic lactams were designed as neutral endopeptidase 24.11 (NEP) inhibitors. Docking studies were carried out in a model of thermolysin (TLN) using the MACROMODEL and QXP modeling programs to select suitable ring sizes. These studies predicted that the 11-, 12-, and 13-membered ring macrocyclic lactams would be active in both enzymes TLN and NEP. Good predictability of experimental results, within this series, of binding to thermolysin and to a lesser extent to NEP was observed. A visual comparison, docked at the active site of TLN, is presented for thiorphan, a 10-membered ring macrocycle and an 11-membered ring benzofused macrocyclic lactam. Potent inhibition of both NEP and thermolysin was obtained. The 11-membered ring macrocycle 25a is the most potent inhibitor from this series of compounds (TLN IC50 = 68 nM; NEP IC50 = 0.9 nM). The effects of prodrug 44b administered at 10 mg/kg po on plasma atrial natriuretic peptide (ANP) levels in conscious rats was greater than 200% over a 4 h period.

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).…”

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.…”

The Synthesis of Macrocycles for Drug Discovery

“…[11][12][13][14][15] Some of these reagents are now available on polymer supports for ease of use in parallel synthesis and diversity investigations. 15 Macrolactamization, not surprisingly, is often the method of choice for peptidomimetic macrocycles and has been successfully employed for a wide range of structures from the small ring inhibitors (5) of neutral endopeptidase 24.11 (NEP) 16,17 (Figure 11.1, ring closure site indicated with reagent used for cyclization (HATU (2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate), FDPP (pentafluorophenyl diphenylphosphinate), TCBC (2,4,6-trichlorobenzoyl chloride, Yamaguchi's reagent)) to the larger macrocycles (6) pioneered by Robinson as protein epitope mimics (PEM). 18 Two of the more advanced synthetic macrocycles in clinical trials arose from this latter methodology, POL6326, a CXCR4 antagonist currently in Phase II investigations for use in the mobilization and transplantation of stem cells, [19][20][21] and POL7080, an antibiotic that is in a Phase II clinical study for the treatment of life-threatening Pseudomonas infections.…”