Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases.

Abstract

A diverse set of 3-aminopyrazolo[3,4-d]pyrimidinones was designed and synthesized. The structure-activity relationships of these polycyclic compounds as phosphodiesterase 1 (PDE1) inhibitors were studied along with their physicochemical and pharmacokinetic properties. Systematic optimizations of this novel scaffold culminated in the identification of a clinical candidate, (6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-3-(phenylamino)-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(2H)-one phosphate (ITI-214), which exhibited picomolar inhibitory potency for PDE1, demonstrated excellent selectivity against all other PDE families and showed good efficacy in vivo. Currently, this investigational new drug is in Phase I clinical development and being considered for the treatment of several indications including cognitive deficits associated with schizophrenia and Alzheimer's disease, movement disorders, attention deficit and hyperactivity disorders, and other central nervous system (CNS) and non-CNS disorders.

DOI: 10.1021/acs.jmedchem.5b01751

Cite this paper

@article{Li2016DiscoveryOP, title={Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases.}, author={Peng Li and Hailin Zheng and Jun Zhao and Lei Zhang and Wei Yao and Hongwen Zhu and Jill Beard and Koh Ida and Weston Lane and Gyorgy P Snell and Satoshi Sogabe and Charles J Heyser and Gretchen L. Snyder and Joseph P. Hendrick and Kimberly E. Vanover and Robert E. Davis and Lawrence Paul Wennogle}, journal={Journal of medicinal chemistry}, year={2016}, volume={59 3}, pages={1149-64} }