Yamashita Dennis S, Marquis Robert W, Xie Ren, Nidamarthy Sirishkumar D, Oh Hye-Ja, Jeong Jae U, Erhard Karl F, Ward Keith W, Roethke Theresa J, Smith Brian R, Cheng H-Y, Geng Xiaoliu, Lin Fan, Offen Priscilla H, Wang Bing, Nevins Neysa, Head Martha S, Haltiwanger R Curtis, Narducci Sarjeant Amy A, Liable-Sands Louise M, Zhao Baoguang, Smith Ward W, Janson Cheryl A, Gao Enoch, Tomaszek Thaddeus, McQueney Michael, James Ian E, Gress Catherine J, Zembryki Denise L, Lark Michael W, Veber Daniel F
Department of Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville Rd, Collegeville, Pennsylvania 19426, USA.
J Med Chem. 2006 Mar 9;49(5):1597-612. doi: 10.1021/jm050915u.
The syntheses, in vitro characterizations, and rat and monkey in vivo pharmacokinetic profiles of a series of 5-, 6-, and 7-methyl-substituted azepanone-based cathepsin K inhibitors are described. Depending on the particular regiochemical substitution and stereochemical configuration, methyl-substituted azepanones were identified that had widely varied cathepsin K inhibitory potency as well as pharmacokinetic properties compared to the 4S-parent azepanone analogue, 1 (human cathepsin K, K(i,app) = 0.16 nM, rat oral bioavailability = 42%, rat in vivo clearance = 49.2 mL/min/kg). Of particular note, the 4S-7-cis-methylazepanone analogue, 10, had a K(i,app) = 0.041 nM vs human cathepsin K and 89% oral bioavailability and an in vivo clearance rate of 19.5 mL/min/kg in the rat. Hypotheses that rationalize some of the observed characteristics of these closely related analogues have been made using X-ray crystallography and conformational analysis. These examples demonstrate the potential for modulation of pharmacological properties of cathepsin inhibitors by substituting the azepanone core. The high potency for inhibition of cathepsin K coupled with the favorable rat and monkey pharmacokinetic characteristics of compound 10, also known as SB-462795 or relacatib, has made it the subject of considerable in vivo evaluation for safety and efficacy as an inhibitor of excessive bone resorption in rat, monkey, and human studies, which will be reported elsewhere.
描述了一系列5-、6-和7-甲基取代的氮杂环庚烷酮基组织蛋白酶K抑制剂的合成、体外特性以及大鼠和猴子体内药代动力学概况。根据特定的区域化学取代和立体化学构型，与4S-母体氮杂环庚烷酮类似物1（人组织蛋白酶K，K(i,app)=0.16 nM，大鼠口服生物利用度=42%，大鼠体内清除率=49.2 mL/min/kg）相比，鉴定出甲基取代的氮杂环庚烷酮具有广泛不同的组织蛋白酶K抑制效力以及药代动力学性质。特别值得注意的是，4S-7-顺式甲基氮杂环庚烷酮类似物10对人组织蛋白酶K的K(i,app)=0.041 nM，口服生物利用度为89%，在大鼠体内清除率为19.5 mL/min/kg。已利用X射线晶体学和构象分析对这些密切相关类似物的一些观察到的特性进行合理化解释。这些实例证明了通过取代氮杂环庚烷酮核心来调节组织蛋白酶抑制剂药理性质的潜力。化合物10（也称为SB-462795或雷卡替布）对组织蛋白酶K的高效抑制作用以及在大鼠和猴子中良好的药代动力学特性，使其成为大鼠、猴子和人体研究中作为过度骨吸收抑制剂进行大量体内安全性和有效性评估的对象，相关研究将在其他地方报道。
