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

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Administration of an extract from the powdered root of the plant Withania somnifera (Family: Solanaceae) enhanced the levels of Interferon gamma (IFN-gamma) (75.87 pg/ml), Interleukin-2 (IL-2) (14.16 pg/ml) and Granulocyte macrophage colony stimulating factor (GM-CSF) (49.22 pg/ml) in normal Balb/c mice. The lowered levels of IFN gamma--(30 pg/ml), IL-2 (4.5 pg/ml) and GM-CSF (19.12 pg/ml) after treatment with cyclophosphamide (CTX) was reversed by the administration of Withania somnifera extract (IFN gamma--74 pg/ml; IL-2 7.5 pg/ml; GM-CSF 35.47 pg/ml). Withania extract lowered the levels of Tumour necrosis factor alpha (TNF alpha) production. Administration of bonemarrow cells from donor mice treated with Withania extract increased the spleen nodular colonies in irradiated mice (8.33) compared to those treated with normal bonemarrow cells (3.03). The number of nodular colonies increased significantly when these animals were continued with Withania extract treatment. These results indicate the immunopotentiating and myeloprotective effect of Withania somnifera as seen from the enhancement of cytokine production and stem cell proliferation and its differentiation.

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