The discovery of avanafil for the treatment of erectile dysfunction: A novel pyrimidine-5-carboxamide derivative as a potent and highly selective phosphodiesterase 5 inhibitor

Sakamoto, Takabumi; Koga, Yasuo; Hikota, Masataka; Matsuki, Kenji; Murakami, Michino; Kikkawa, Kohei; Fujishige, Kotomi; Kotera, Jun; Omori, Kenji; Morimoto, Hiroshi; Yamada, Kazuo

doi:10.1016/j.bmcl.2014.10.008

Cited by 26 publications

(25 citation statements)

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“…Numerous scientific approaches appearing in medicinal chemistry area cover different experimental techniques along with computer-aided molecular modeling methods in the course of discovering more potent and selective PDE5 inhibitors. Especially, structure–activity relationship (SAR) studies are very helpful where distinct chemical synthesis routes guided by oral bioavailability, solubility, membrane permeability, toxicity, lipophilicity and other pharmacokinetic and physiochemical tests have given rise to novel potent compounds to emerge as PDE5 inhibitors 8 , 13–16 , 18–23 , 25–28 , 40 , 41 . Scaffold hopping strategies have been implemented in designing structurally different – in terms of core architecture – novel compounds 9 .…”

Section: Introductionmentioning

confidence: 99%

Investigation of PDE5/PDE6 and PDE5/PDE11 selective potent tadalafil-like PDE5 inhibitors using combination of molecular modeling approaches, molecular fingerprint-based virtual screening protocols and structure-based pharmacophore development

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Tüzün

Durdağı

2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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The essential biological function of phosphodiesterase (PDE) type enzymes is to regulate the cytoplasmic levels of intracellular second messengers, 3′,5′-cyclic guanosine monophosphate (cGMP) and/or 3′,5′-cyclic adenosine monophosphate (cAMP). PDE targets have 11 isoenzymes. Of these enzymes, PDE5 has attracted a special attention over the years after its recognition as being the target enzyme in treating erectile dysfunction. Due to the amino acid sequence and the secondary structural similarity of PDE6 and PDE11 with the catalytic domain of PDE5, first-generation PDE5 inhibitors (i.e. sildenafil and vardenafil) are also competitive inhibitors of PDE6 and PDE11. Since the major challenge of designing novel PDE5 inhibitors is to decrease their cross-reactivity with PDE6 and PDE11, in this study, we attempt to identify potent tadalafil-like PDE5 inhibitors that have PDE5/PDE6 and PDE5/PDE11 selectivity. For this aim, the similarity-based virtual screening protocol is applied for the “clean drug-like subset of ZINC database” that contains more than 20 million small compounds. Moreover, molecular dynamics (MD) simulations of selected hits complexed with PDE5 and off-targets were performed in order to get insights for structural and dynamical behaviors of the selected molecules as selective PDE5 inhibitors. Since tadalafil blocks hERG1 K channels in concentration dependent manner, the cardiotoxicity prediction of the hit molecules was also tested. Results of this study can be useful for designing of novel, safe and selective PDE5 inhibitors.

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Section: Introductionmentioning

confidence: 99%

Investigation of PDE5/PDE6 and PDE5/PDE11 selective potent tadalafil-like PDE5 inhibitors using combination of molecular modeling approaches, molecular fingerprint-based virtual screening protocols and structure-based pharmacophore development

Kayık

Tüzün

Durdağı

2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Avanafil (1) [13][14][15] is a PDE5 selective inhibitor used as a treatment for erectile dysfunction, discovered by our company. We noticed the sequence homology between PDE5 and PDE10A (whole: 27%, catalytic domain: 46%) 16) and searched our PDE5 inhibitor library to discover PDE10A inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor

Kadoh¹,

Miyoshi²,

Matsumura³

et al. 2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.

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“…Classical drugs are sildenafil, vardenafil, and tadalafil, while the newest one is avanafil. 7 , 8 These have many unwanted side effects, such as headache, nausea, dizziness. In second-line treatment, intracavernosal or intraurethral alprostadil therapy is used in patients who do not respond or are contraindicated for PDE5 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Papaverine hydrochloride containing nanostructured lyotropic liquid crystal formulation as a potential drug delivery system for the treatment of erectile dysfunction

Berkó

Zsikó

Deák

et al. 2018

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PurposePapaverine hydrochloride (PaHCl) is an old, well-known drug with spasmolytic activity but it has therapeutic effect in erectile dysfunction, too. As an intracavernous injection, it is not used in urologic clinics today because the side effects of the injection are pain, scarring or priapism. Our aim was to develop and test a topical semi-solid preparation containing PaHCl that would provide an alternative administration option by eliminating the undesirable side effects of the injection.Materials and methodsLyotropic liquid crystal (LLC) systems were formulated as a semi-solid preparation with different concentrations of PaHCl. The characterization of the LLC structure was performed by polarization microscopy using a Leica image analyzer and rheological measurements. The drug diffusion and penetration tests were performed with in vitro synthetic membrane and an ex vivo human epidermis, using Franz diffusion cell to test the skin penetration of PaHCl. Human skin was investigated by Raman microscope to visualize the Active Pharmaceutical Ingredient (API) in different skin layers.ResultsThe results of diffusion and penetration showed reverse concentration dependency. The in vitro and ex vivo studies correlated with each other and the results of Raman microscopy. The LLC structure influenced the penetration results, the lower viscosity and lamellar structure increased penetration through the skin.ConclusionBased on our results, a PaHCl containing topically used LLC formulation may be a suitable and effective alternative to the injectable formulation.

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The discovery of avanafil for the treatment of erectile dysfunction: A novel pyrimidine-5-carboxamide derivative as a potent and highly selective phosphodiesterase 5 inhibitor

Cited by 26 publications

References 9 publications

Investigation of PDE5/PDE6 and PDE5/PDE11 selective potent tadalafil-like PDE5 inhibitors using combination of molecular modeling approaches, molecular fingerprint-based virtual screening protocols and structure-based pharmacophore development

Investigation of PDE5/PDE6 and PDE5/PDE11 selective potent tadalafil-like PDE5 inhibitors using combination of molecular modeling approaches, molecular fingerprint-based virtual screening protocols and structure-based pharmacophore development

Discovery of 2-[(<i>E</i>)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-<i>N</i>-(tetrahydro-2<i>H</i>-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor

Papaverine hydrochloride containing nanostructured lyotropic liquid crystal formulation as a potential drug delivery system for the treatment of erectile dysfunction

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