Department of Ocular Biology, Pfizer Global R & D, San Diego, CA 92121, USA.
Exp Eye Res. 2011 Sep;93(3):256-64. doi: 10.1016/j.exer.2011.02.015. Epub 2011 Mar 3.
Better control of intraocular pressure (IOP) is the most effective way to preserve visual field function in glaucomatous patients. While prostaglandin FP analogs are leading the therapeutic intervention for glaucoma, new target classes also are being identified with new lead compounds being developed for IOP reduction. One target class currently being investigated includes the prostaglandin EP receptor agonists. Recently PF-04217329 (Taprenepag isopropyl), a prodrug of CP-544326 (active acid metabolite), a potent and selective EP(2) receptor agonist, was successfully evaluated for its ocular hypotensive activity in a clinical study involving patients with primary open angle glaucoma. In the current manuscript, the preclinical attributes of CP-544326 and PF-0421329 have been described. CP-544326 was found to be a potent and selective EP(2) agonist (IC(50) = 10 nM; EC(50) = 2.8 nM) whose corneal permeability and ocular bioavailability were significantly increased when the compound was dosed as the isopropyl ester prodrug, PF-04217329. Topical ocular dosing of PF-04217329 was well tolerated in preclinical species and caused an elevation of cAMP in aqueous humor/iris-ciliary body indicative of in vivo EP(2) target receptor activation. Topical ocular dosing of PF-04217329 resulted in ocular exposure of CP-544326 at levels greater than the EC(50) for the EP(2) receptor. PF-04217329 when dosed once daily caused between 30 and 50% IOP reduction in single day studies in normotensive Dutch-belted rabbits, normotensive dogs, and laser-induced ocular hypertensive cynomolgus monkeys and 20-40% IOP reduction in multiple day studies compared to vehicle-dosed eyes. IOP reduction was sustained from 6 h through 24 h following a single topical dose. In conclusion, preclinical data generated thus far appear to support the clinical development of PF-04217329 as a novel compound for the treatment of glaucoma.
更好地控制眼内压（IOP）是保护青光眼患者视野功能的最有效方法。虽然前列腺素 FP 类似物是治疗青光眼的主要治疗手段，但新的靶类也在被确定，新的先导化合物也在被开发用于降低 IOP。目前正在研究的一个靶类包括前列腺素 EP 受体激动剂。最近，PF-04217329（Taprenepag 异丙酯），CP-544326（活性酸代谢物）的前药，一种有效的和选择性的 EP(2)受体激动剂，在一项涉及原发性开角型青光眼患者的临床研究中成功评估了其降眼压活性。在当前的手稿中，描述了 CP-544326 和 PF-0421329 的临床前特征。CP-544326 是一种有效的和选择性的 EP(2)激动剂（IC(50)=10 nM; EC(50)=2.8 nM），当化合物作为异丙酯前药 PF-04217329 给药时，其角膜通透性和眼部生物利用度显著增加。PF-04217329 在临床前物种中局部眼部给药耐受性良好，并导致房水中 cAMP 升高，提示体内 EP(2)靶受体激活。PF-04217329 局部眼部给药导致 CP-544326 的眼部暴露水平高于 EP(2)受体的 EC(50)。PF-04217329 每日给药一次，可使正常血压的荷兰兔、正常血压的狗和激光诱导的高眼压食蟹猴的眼压在单天研究中降低 30%至 50%，与载体给药眼相比，多日研究中降低 20%至 40%。眼压降低可在单次局部给药后 6 小时至 24 小时持续。总之，迄今为止产生的临床前数据似乎支持 PF-04217329 作为一种治疗青光眼的新型化合物的临床开发。
