Macrocycles inhibitors

Further optimization of the tetrapeptide series led to very potent inhibitors allowing for size reduction to tiipeptides (Figure 2.5) [104]. Further structural studies revealed that macrocyclization can improve potency by constraining the vinyl-ACCA into the correct conformation for binding [42, 105]. In this series of macrocyclic inhibitors, the cyclopropyl PI moiety is... 

Figure 16 (a) Structures of adenylation domain intermediates and inhibitors aminoacyl-sulfamoyl adenosine (AMS) and cisoid -like macrocyclic inhibitor, (b) Alkyne-functionalized chemical probe for NRPS A and PCP domains, (c) Structure of aminoacyl PCP, SNAC substrate analogue, and hydrolytically stable phosphopantetheinyl analogue, (d) Structure of vinylsulfonamide probe. R represents a peptide component and R an amino acid side chain. 

Meyer, J.H., and Bartlett, P.A., Macrocyclic inhibitors of penicillopepsin. Part 1. Design, synthesis, and evaluation of an inhibitor bridged between Pl and P3, J. Am. Chem. Soc., 120, 4600, 1998. Noguchi, H., Aoyama, T., and Shioiri, T., Total synthesis of analogs of topostin B, a DNA topoi-somerase 1 inhibitor. Part 1. Synthesis of fragments of topostin B-1 analogs. Tetrahedron, 51, 10531, 1995. 

Macrocyclic inhibitors of peniciUopepsin. 2. X-Ray cristallo-graphic analyses of peniciUopepsin complexed with a P3-P1 macrocyclic peptidyl inhibitor and its two acyclic analogues. J. Am. Chem. Soc. 120 4610-4621. 

Tyndall, J.D.A., Reid, R.C., Tyssen, D.P., Jatdine, D.K., Todd, B., etal. (2000) Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease. J. Med. Chem. 43 3495—3504. 

Francesco M. E. D, Dessole G, Nizi E, Pace P, Koch U, Fiore F, Pesci S, Muzio J. D, Monteagudo E, Rowley M, Summa V. Novel Macrocyclic Inhibitors of Hepatitis C NS3/4A Protease Featuring a 2-Amino-1,3-thiazole as a P4 Carbamate Replacement, J. Med. Chem. 2009. p. 7014 - 7028. DOI 10.1021/jm900524b... 

Smith WW, Bardett PA (1998) Macrocyclic inhibitors of penicillopepsin. 3. Design, synthesis, and evaluation of an inhibitor bridged between P2 and PI . J Am Chem Soc 120 4622-4628... 

In the first iteration of macrocyclic inhibitor design, the SAR of a series of 11- to 14-membered ring benzamido-tetrahydroindolones was explored and... 

Class IV iV-Middle Domain Hsp90 Macrocyclic Inhibitors... 

Macrocyclic Inhibitors of Zinc-dependent Histone Deacetylases (HDACs)... 

---