Effect of PF-04217329 a prodrug of a selective prostaglandin EP2 agonist on intraocular pressure in preclinical models of glaucoma
Effect of PF-04217329 a prodrug of a selective prostaglandin EP2 agonist on intraocular pressure in preclinical models of glaucoma
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DOI：
10.1016/j.exer.2011.02.015
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发表时间：
2011-09-01
影响因子：
3.4
通讯作者：
Krauss, Achim
中科院分区：
文献类型：
--
作者：
Prasanna, Ganesh;Carreiro, Samantha;Krauss, Achim
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类似物是青光眼治疗干预的主要药物，但新的靶向类别也正在被确定，新的先导化合物正在开发用于降低IOP。目前正在研究的一个目标类别包括前列腺素EP受体激动剂。最近，在一项涉及原发性开角型青光眼患者的临床研究中，成功评价了CP-544326（活性酸代谢产物）的前药PF-04217329（Taprenepag isopropyl）（一种强效和选择性EP 2受体激动剂）的眼部扩张活性。在当前手稿中，描述了CP-544326和PF-0421329的临床前属性。发现CP-544326是一种强效和选择性EP 2激动剂（IC 50 = 10 nM; EC 50 = 2.8 nM），当该化合物作为异丙酯前药PF-04217329给药时，其角膜渗透性和眼部生物利用度显著增加。PF-04217329眼部局部给药在临床前种属中耐受良好，并导致房水/虹膜-睫状体中cAMP升高，表明体内EP 2靶受体活化。PF-04217329眼部局部给药导致CP-544326的眼部暴露水平高于EP 2受体的EC 50。与溶剂给药眼相比，PF-04217329每日一次给药在血压正常的荷兰带兔、血压正常的犬和激光诱导高眼压食蟹猴的单日研究中导致IOP降低30 - 50%，在多日研究中导致IOP降低20-40%。单次局部给药后，IOP降低持续6 h至24 h。总之，迄今为止生成的临床前数据似乎支持PF-04217329作为治疗青光眼的新型化合物的临床开发。(C)2011爱思唯尔有限公司保留所有权利。
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 EP2 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 EP2 agonist (IC50 = 10 nM; EC50 = 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 EP2 target receptor activation. Topical ocular dosing of PF-04217329 resulted in ocular exposure of CP-544326 at levels greater than the EC50 for the EP2 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. (C) 2011 Elsevier Ltd. All rights reserved.