Macrocyclic constrained inhibitor design has become of great interest recently. A number of potent, orally bioavailable macrocyclic inhibitors targeting farnesyltransferase, thrombin, metalloproteases, HCV protease, and HIV protease have been discovered (35-42). Since the lead structures all have extended and highly flexible backbones, macrocyclization is one way to reduce the number of potential conformers of the leads while still preserving all the necessary binding elements. The increased the rigidity may also allow the inhibitors to adopt the optimal binding conformation that may have higher energy barrier for a free rotate solution structure to overcome.

Detailed SAR studies of a series of macrocyclic famesyltransferase inhibitors were reported following the early discovered macrocyclic lead (43,44). Compared with previous linear leads such as 46, macrocyclic inhibitors in this series showed significant increases in potency. Compound 48 also had improved pharmacokinetic properties and lowered inhibition of hERG channel. After X-ray crystallography and NMR spectroscopy studies of these inhibitors, the report concluded that the improvements in iv half-lives due to lower plasma clearance appeared to correlate with the rigidity of the molecules.

Tumor necrosis factor-a converting enzyme (TACE) is responsible for the conversion of the pro-TNF-a to soluble TNF-a that plays a central role in symptoms of a variety of infectious, autoimmune and inflammatory disorders. Analogous to the development of the macrocyclic MMP inhibitors 50 as a macrocyclic mimic of marimast 49, the design, synthesis and SAR of a new class of macrocyclic hydroxamic acid TACE inhibitors has been reported (45). Additional SAR studies following the early macrocyclic lead 51, the undesired cross activities toward MMP1, MMP2 and MMP9 were suppressed without compromising the TACE activity (46). Compound 52 showed an IC5o of 70 nM in human whole blood and more than 100fold selectivity over a panel of 11 MMPs.

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