Neuroscience Chemistry, Pfizer Global R&D, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA.
Bioorg Med Chem Lett. 2011 Sep 15;21(18):5475-9. doi: 10.1016/j.bmcl.2011.06.117. Epub 2011 Jul 2.
The discovery, of a series of 2-Cl-5-heteroaryl-benzamide antagonists of the P2X(7) receptor via parallel medicinal chemistry is described. Initial analogs suffered from poor metabolic stability and low Vd(ss). Multi parametric optimization led to identification of pyrazole 39 as a viable lead with excellent potency and oral bioavailability. Further attempts to improve the low Vd(ss) of 39 via introduction of amines led to analogs 40 and 41 which maintained the favorable pharmacology profile of 39 and improved Vd(ss) after iv dosing. But these analogs suffered from poor oral absorption, probably driven by poor permeability.
通过平行药物化学方法，发现了一系列 2-Cl-5-杂芳基苯甲酰胺 P2X(7)受体拮抗剂。最初的类似物由于代谢稳定性差和 Vd(ss)低而受到影响。多参数优化导致发现吡唑 39 是一种具有优异效力和口服生物利用度的可行先导化合物。进一步尝试通过引入胺来提高 39 的低 Vd(ss)，得到了类似物 40 和 41，它们保持了 39 的有利药理学特性，并在静脉注射后提高了 Vd(ss)。但是这些类似物口服吸收不良，可能是由于渗透性差所致。
