Substituted Pyrazolopyridines as Potent and Selective PDE5 Inhibitors:  Potential Agents for Treatment of Erectile Dysfunction

Yu, Ga-Er; Mason, Helen J.; Wu, Ximao; Wang, Jian; Chong, Samuel S.; Dorough, Gary; Henwood, Andrew; Pongrac, Ronald; Seliger, Laurie; He, Bin; Normandin, Diane E.; Adam, Leonard P.; Krupinski, John; Macor, John E.

doi:10.1021/jm0155042

Cited by 43 publications

(18 citation statements)

References 11 publications

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“…1C); 4) isoquinolinone, naphthyridinone and pyridopyrazinone derivatives (Fig. 1D) [25–30]. Among them, compounds based on a quinoline structure have demonstrated to be potent inhibitors with a selectivity for PDE1 through 6 and unknown selectivity for the remaining PDEs [28].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of quinoline derivatives: Discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease

Fiorito

Saeed

Zhang

et al. 2013

European Journal of Medicinal Chemistry

102

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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 IC50 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.

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Section: Introductionmentioning

confidence: 99%

Synthesis of quinoline derivatives: Discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease

Fiorito

Saeed

Zhang

et al. 2013

European Journal of Medicinal Chemistry

102

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“…12) was reported as a potent PDE5 inhibitor in a patent from Sanofi-Winthrop. 80 Using 53 as a template for a substructure search, scientists from Bristol-Myers Squibb 81 chose a series of pyrazolopyridines for PDE5 screening. This effort identified 54 (PDE5 IC 50 ¼ 180 nM) as a nonselective PDE5 inhibitor with modest potency.…”

Section: E Sar Of Pyrazolopyridines and Pyrazolopyridopyridazinesmentioning

confidence: 99%

Phosphodiesterase 5 (PDE 5) inhibitors for the treatment of male erectile disorder: Attaining selectivity versus PDE6

Pissarnitski¹

2005

Medicinal Research Reviews

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The role of phosphodiesterase type 5 (PDE5) in the mechanism of male erection has been well understood, and several drugs inhibiting this enzyme are being used for the treatment of erectile dysfunction (ED). Discovery of inhibitors with improved selectivity versus other PDE isozymes could lead to drugs with improved safety profile. Achievement of selectivity versus PDE6, co-inhibition of which results in disturbances of color perception, remains the most challenging aspect of current drug discovery programs. The present review describes several case studies, where significant (>100 fold) selectivity versus PDE6 has been attained via investigation of structure-activity relationships (SAR). Special attention is given to the chemical routes leading to novel chemotypes and allowing efficient exploration of their SAR's. Strategies for attaining inhibitor selectivity discussed below may be applicable for other drug discovery programs.

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“…Pyrazolo[3,4‐ b ]pyridine ring system is a privileged substructure in the many molecules because of its various biologically activties, such as antiallergic, antiproliferative, antihypotensive, anti‐antimicrobial, and antiasthmatic activities . Moreover, lots of compounds with pyrazolo[3,4‐ b ]pyridine scaffold are also the important bioactive molecules, act as vasodilators, cyclin‐dependent kinase 1 inhibitors, respectively.…”

Section: Introductionmentioning

confidence: 99%

Efficient reactions for the synthesis of pyrazolo[3,4‐b]pyridine and pyrano[2,3‐c]pyrazole derivatives from N‐methyl‐1‐(methylthio)‐2‐nitroethen‐1‐amine

Zhu

et al. 2020

Journal of Heterocyclic Chem

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The efficient and novel method for the synthesis of pyrazolo[3,4‐b]pyridine and pyrano[2,3‐c]pyrazole derivatives from the multicomponent reaction of aromatic aldehydes (isatins), N‐methyl‐1‐(methylthio)‐2‐nitroethen‐1‐amine, and 3‐aminopyrazole or methyl 3‐hydroxy‐1H‐pyrazole‐5‐carboxylate under normal laboratory conditions was reported in this research. The advantages of this research are wide range of substrates, high yields, and simple operation.

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Substituted Pyrazolopyridines as Potent and Selective PDE5 Inhibitors: Potential Agents for Treatment of Erectile Dysfunction

Cited by 43 publications

References 11 publications

Synthesis of quinoline derivatives: Discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease

Synthesis of quinoline derivatives: Discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease

Phosphodiesterase 5 (PDE 5) inhibitors for the treatment of male erectile disorder: Attaining selectivity versus PDE6

Efficient reactions for the synthesis of pyrazolo[3,4‐b]pyridine and pyrano[2,3‐c]pyrazole derivatives from N‐methyl‐1‐(methylthio)‐2‐nitroethen‐1‐amine

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