title: Synthesis of quinoline derivatives: discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease.
abstract: Phosphodiesterase type 5 (PDE5) mediates the degradation of cGMP in a variety of tissues including brain. Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory. Thus, PDE5 inhibitors (PDE5Is) are thought to be promising new therapeutic agents for the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss. To explore this possibility, a series of quinoline derivatives were synthesized and evaluated. We found that compound 7a selectively inhibits PDE5 with an IC(50) of 0.27 nM and readily crosses the blood brain barrier. In an in vivo mouse model of AD, compound 7a rescues synaptic and memory defects. Quinoline-based, CNS-permeant PDE5Is have potential for AD therapeutic development.
authors: Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630 W 168th St., New York, NY 10032, USA.
authors: Jole
authors: J
authors: Fiorito
authors: Faisal
authors: F
authors: Saeed
authors: Hong
authors: H
authors: Zhang
authors: Agnieszka
authors: A
authors: Staniszewski
authors: Yan
authors: Y
authors: Feng
authors: Yitshak I
authors: YI
authors: Francis
authors: Sudha
authors: S
authors: Rao
authors: Devarshi M
authors: DM
authors: Thakkar
authors: Shi-Xian
authors: SX
authors: Deng
authors: Donald W
authors: DW
authors: Landry
authors: Ottavio
authors: O
authors: Arancio
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D004195:Disease Models, Animal; D055808:Drug Discovery; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D058986:Phosphodiesterase 5 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D011804:Quinolines; C037219:quinoline