Design, Synthesis and Biological Activity of β‐Carboline‐Based Type‐5 Phosphodiesterase Inhibitors.

Maw, Graham N.; Allerton, Charlotte; Gbekor, Eugene; Million, William A.

doi:10.1002/chin.200329132

Cited by 13 publications

(28 citation statements)

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“…16,23,25 The physiological function of PDE11A is poorly understood. It was reported that tadalafil had 5.5-and 40-fold selectivity against PDE11A1 26 and PDE11A4, 27 respectively. Studies in dogs showed that when administrated daily for 6 and 12 months, there were changes in seminiferous epithelium that resulted in a decrease in spermatogenesis in some dogs.…”

Section: Discussionmentioning

confidence: 99%

JNJ-10280205 and JNJ-10287069: novel PDE5 inhibitors as clinical candidates for erectile dysfunction

et al. 2006

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Phosphodiesterase 5 (PDE5) inhibitors are efficacious in treating patients with erectile dysfunction. New PDE5 inhibitors with different selectivity and pharmacokinetic profiles have been vigorously pursued. Here we report two novel, potent, and selective PDE5 inhibitors, JNJ-10280205 and JNJ-10287069, with K i values of 0.05 and 0.12 nM, respectively. Both compounds displayed superior selectivity against PDE1-4 and -6 when compared to sildenafil. In the anesthetized dogs, JNJ-10280205 and JNJ-10287069 exhibited similar efficacy as sildenafil in enhancing erectile functions, with no significant effect on cardiovascular parameters. Pharmacokinetic studies showed that JNJ-10287069 had better oral bioavailability than JNJ-10280205 in several animal species. In vitro study suggested that cytochrome P450 (CYP) 3A4 played a major role in the metabolism of both compounds. The compounds inhibited some of the CYP450 enzymes and the human ether-a-go-go (HERG) channel at much higher concentrations than that required to inhibit PDE5, thus, no cross inhibition would be expected at therapeutic doses. Both compounds are suitable clinical candidates.

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Section: Discussionmentioning

confidence: 99%

JNJ-10280205 and JNJ-10287069: novel PDE5 inhibitors as clinical candidates for erectile dysfunction

et al. 2006

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“…71 The physiological significance of PDE11 inhibition is not clearly understood but could have a role in sperm function. Protein localization of PDE11 in man and mouse, coupled with the known role for cGMP and cAMP in sperm physiology and testosterone production, suggests a local role for PDE11 in testis development and/or spermatogenesis.…”

Section: B Development Of B-carboline Scaffoldmentioning

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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“…Since the X-ray structure of PDE11 was not available, ligand-based homology modeling technique was applied to explore the 3D structure of PDE11 [27]. Consistent with the sequence similarity of PDE11 and PDE5, several tadalail analogs (PDE5 ligands) showed binding ainity to PDE11 too [28][29][30]. Thus, the 3D structure of PDE11 was built on the basis of PDE5-tadalail complex using homology modeling technique [31].…”

Section: Pde11 Inhibitorsmentioning

confidence: 99%

Computational Approaches in the Development of Phosphodiesterase Inhibitors

Gaurav¹,

Xing²,

Al-Nema³

2017

Quantitative Structure-Activity Relationship

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Computational drug design tools have become indispensable in the quest for new drugs. There is hardly any drug discovery program where computational methods are not employed, be it structure-based or ligand-based methods. Numerous drug targets have been explored for discovery of new drugs using computational methods. In recent times, discovery of newer and selective phosphodiesterase as medications for inlammatory disorders, CNS disorders, and many other diseases has been the focus of many research groups worldwide. Most of these groups have employed computational methods of drug design and discovery at diferent stages of their research. This chapter reviews the reported application of computational methods used in the discovery and development of phosphodiesterase inhibitors.

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Design, Synthesis and Biological Activity of β‐Carboline‐Based Type‐5 Phosphodiesterase Inhibitors.

Cited by 13 publications

References 1 publication

JNJ-10280205 and JNJ-10287069: novel PDE5 inhibitors as clinical candidates for erectile dysfunction

JNJ-10280205 and JNJ-10287069: novel PDE5 inhibitors as clinical candidates for erectile dysfunction

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

Computational Approaches in the Development of Phosphodiesterase Inhibitors

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