Marquis Robert W, Lago Amparo M, Callahan James F, Rahman Attiq, Dong Xiaoyang, Stroup George B, Hoffman Sandra, Gowen Maxine, DelMar Eric G, Van Wagenen Bradford C, Logan Sarah, Shimizu Scott, Fox John, Nemeth Edward F, Roethke Theresa, Smith Brian R, Ward Keith W, Bhatnagar Pradip
Department of Medicinal Chemistry, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.
J Med Chem. 2009 Nov 12;52(21):6599-605. doi: 10.1021/jm900563e.
When administered as a single agent to rats, the previously reported calcium receptor antagonist 3 elicited a sustained elevation of plasma PTH resulting in no increase in overall bone mineral density. The lack of a bone building effect for analogue 3 was attributed to the large volume of distribution (V(dss)(rat) = 11 L/kg), producing a protracted plasma PTH profile. Incorporation of a carboxylic acid functionality into the amino alcohol template led to the identification of 12 with a lower volume of distribution (V(dss)(12) = 1.18 L/kg) and a shorter half-life. The zwitterionic nature of antagonist 12 necessitated the utility of an ester prodrug approach to increase overall permeability. Antagonist 12 elicited a rapid and transient increase in circulating levels of PTH following oral dosing of the ester prodrug 11 in the dog. The magnitude and duration of the increases in plasma levels of PTH would be expected to stimulate new bone formation.
当作为单一药剂给予大鼠时，先前报道的钙受体拮抗剂3引起血浆甲状旁腺激素（PTH）持续升高，导致总体骨矿物质密度没有增加。类似物3缺乏骨生成作用归因于其较大的分布容积（V(dss)(大鼠)=11 L/kg），产生了持久的血浆PTH曲线。将羧酸官能团引入氨基醇模板导致鉴定出分布容积较低（V(dss)(12)=1.18 L/kg）且半衰期较短的化合物12。拮抗剂12的两性离子性质使得需要采用酯前药方法来提高总体渗透性。在犬口服酯前药11后，拮抗剂12引起循环中PTH水平快速且短暂升高。PTH血浆水平升高的幅度和持续时间预计会刺激新骨形成。
