Application of Structure-Based Drug Design and Parallel Chemistry to Identify Selective, Brain Penetrant, In Vivo Active Phosphodiesterase 9A Inhibitors

被引：50

作者：

Claffey, Michelle M. ^{[1
]}

Helal, Christopher J. ^{[1
]}

Verhoest, Patrick R. ^{[1
]}

Kang, Zhijun ^{[1
]}

Fors, Kristina S. ^{[1
]}

Jung, Stanley ^{[1
]}

Zhong, Jiaying ^{[1
]}

Bundesmann, Mark W. ^{[1
]}

Hou, Xinjun ^{[1
]}

Lui, Shenping ^{[1
]}

Kleiman, Robin J. ^{[1
]}

Vanase-Frawley, Michelle ^{[1
]}

Schmidt, Anne W. ^{[1
]}

Menniti, Frank ^{[1
]}

Schmidt, Christopher J. ^{[1
]}

Hoffman, William E. ^{[1
]}

Hajos, Mihaly ^{[1
]}

McDowell, Laura ^{[1
]}

O'Connor, Rebecca E. ^{[1
]}

MacDougall-Murphy, Mary ^{[1
]}

Fonseca, Kari R. ^{[1
]}

Becker, Stacey L. ^{[1
]}

Nelson, Frederick R. ^{[1
]}

Liras, Spiros ^{[1
]}

机构：

[1] Pfizer Worldwide Res & Dev, Groton, CT 06340 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 21期

关键词：

CENTRAL-NERVOUS-SYSTEM; CGMP-SPECIFIC PHOSPHODIESTERASE; P-GLYCOPROTEIN; DISCOVERY; SERIES; SCHIZOPHRENIA; PF-04447943; ALIGNMENT; RODENTS; TARGET;

D O I：

10.1021/jm3009635

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer's disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demon: trated free brain/free plasma >= 1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF.

引用

页码：9055 / 9068

页数：14

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