473706-91-1Relevant articles and documents
Design and synthesis of tetracyclic nonpeptidic biaryl nitrile inhibitors of cathepsin K
Setti, Eduardo L.,Venkatraman, Shankar,Palmer, James T.,Xie, Xiaoming,Cheung, Harry,Yu, Walter,Wesolowski, Gregg,Robichaud, Joel
, p. 4296 - 4299 (2008/02/03)
The synthesis and biological profile of a novel series of potent and selective inhibitors of cysteine protease cathepsin K (Cat K) are described. Pharmacokinetic evaluation of 12 indicated that some members of this series could be suitable candidates to develop new orally active therapeutic agents for the treatment of osteoporosis.
Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K
Palmer, James T.,Bryant, Clifford,Wang, Dan-Xiong,Davis, Dana E.,Setti, Eduardo L.,Rydzewski, Robert M.,Venkatraman, Shankar,Tian, Zong-Qiang,Burrill, Leland C.,Mendonca, Rohan V.,Springman, Eric,McCarter, John,Chung, Tobee,Cheung, Harry,Janc, James W.,McGrath, Mary,Somoza, John R.,Enriquez, Philip,Yu, Z. Walter,Strickley, Robert M.,Liu, Liang,Venuti, Michael C.,Percival, M. David,Falgueyret, Jean-Pierre,Prasit, Peppi,Oballa, Renata,Riendeau, Denis,Young, Robert N.,Wesolowski, Gregg,Rodan, Sevgi B.,Johnson, Colena,Kimmel, Donald B.,Rodan, Gideon
, p. 7520 - 7534 (2007/10/03)
We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.
