| Abstract
| - The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitorsof the cysteine protease cathepsin K (EC 3.4.22.38) are described. These compounds showimproved configurational stability of the C-4 diastereomeric center relative to the previouslypublished five- and six-membered ring ketone-based inhibitor series. Studies in this serieshave led to the identification of 20, a potent, selective inhibitor of human cathepsin K (Ki =0.16 nM) as well as 24, a potent inhibitor of both human (Ki = 0.0048 nM) and rat (Ki,app = 4.8nM) cathepsin K. Small-molecule X-ray crystallographic analysis of 20 established the C-4 Sstereochemistry as being critical for potent inhibition and that unbound 20 adopted the expectedequatorial conformation for the C-4 substituent. Molecular modeling studies predicted the higherenergy axial orientation at C-4 of 20 when bound within the active site of cathepsin K, a featuresubsequently confirmed by X-ray crystallography. Pharmacokinetic studies in the rat show 20to be 42% orally bioavailable. Comparison of the transport of the cyclic and acyclic analoguesthrough CaCo-2 cells suggests that oral bioavailability of the acyclic derivatives is limited bya P-glycoprotein-mediated efflux mechanism. It is concluded that the introduction of aconformational constraint has served the dual purpose of increasing inhibitor potency by lockingin a bioactive conformation as well as locking out available conformations which may serve assubstrates for enzyme systems that limit oral bioavailability.
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