Design, synthesis and evaluation of N2,N4-diaminoquinazoline based inhibitors of phosphodiesterase type 5

Pobsuk, Nattakarn; Paracha, Tamkeen Urooj; Chaichamnong, Nattiya; Salaloy, Nattapas; Suphakun, Praphasri; Hannongbua, Supa; Choowongkomon, Kiattawee; Pekthong, Dumrongsak; Chootip, Krongkarn; Ingkaninan, Kornkanok; Gleeson, M. Paul

doi:10.1016/j.bmcl.2018.11.043

Cited by 11 publications

(9 citation statements)

References 29 publications

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“…Despite structural similarity to the α 1 -adrenergic receptor blocker, prazosin, competitive experiments against PE in the rat pulmonary artery model appear to suggest they may function via a different mode of action. The quinazoline compounds displayed a phenotypic response in-line with the PDE-5 inhibitor, sildenafil, which is consistent with their known biochemical activities [26]. This was also consistent with the observations that quinazoline derivatives with greater PDE-5 inhibitory activity generally show improved activity in the vasodilation model.…”

Section: Discussionsupporting

confidence: 83%

“…Quinazoline analogues ( N 2 , N 4 -quinazoline 2,4-diamines) were synthetized and purified to >95% as reported elsewhere [26]. All samples were dissolved in 100% DMSO and diluted with water to obtain the final test concentrations.…”

Section: Methodsmentioning

confidence: 99%

“…Vasodilation properties have been observed [23], mediated via modulation of the alpha 1-adrenergic (α 1 ) receptor [24] and PDE-5 enzyme [25]. We recently reported the preparation and evaluation of N 2 , N 4 - diamino quinazoline analogues as inhibitors of the latter target [26]. The most active compound identified in this study, displayed as PDE-5 IC 50 0.072 µM, exhibited approximately 5-fold selectivity over PDE-6 inhibition and demonstrated ex-vivo vasodilator activity in a rat pulmonary artery model.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, we compared and contrasted the phenotypic response of test compounds against the PDE-5 inhibitor, sildenafil, and the alpha-adrenergic (α 1 ) receptor blocker, prazosin, as a means to better understand their mode of action. Since, N 2 , N 4 - diamino quinazoline analogues are confirmed PDE-5 inhibitors [26], they are structurally similar to α 1 blocker, prazosin, suggesting the latter mechanism may also contribute to their phenotypic response. To this end, the compounds have also been assessed in terms of their competitive performance against the α 1 -adrenergic receptor agonist phenylephrine (PE).…”

Section: Introductionmentioning

confidence: 99%

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Elucidation of Vasodilation Response and Structure Activity Relationships of N2,N4-Disubstituted Quinazoline 2,4-Diamines in a Rat Pulmonary Artery Model

et al. 2019

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Pulmonary arterial hypertension (PAH) is a rare and progressive disease arising from various etiologies and pathogenesis. PAH decreases life expectancy due to pulmonary vascular remodeling, elevation of mean pulmonary arterial pressure, and ultimately progresses to heart failure. While clinical treatments are available to reduce the associated symptoms, a complete cure has yet to be found. Phosphodiesterase-5 (PDE-5) inhibition has been identified as a possible intervention point in PAH treatment. The functional vasodilation response to N2,N4-diamino quinazoline analogues with differing PDE-5 inhibitory activities and varying physicochemical properties were assessed in both endothelium-intact and denuded rat pulmonary arteries to gain greater insight into their mode of action. All analogues produced vasorelaxant effects with EC50s ranging from 0.58 ± 0.22 µM to ˃30 µM. It was observed that vasodilation response in intact vessels was highly correlated with that of denuded vessels. The ~10% drop in activity is consistent with a loss of the nitric oxide mediated cyclic guanosine monophosphate (NO/cGMP) pathway in the latter case. A moderate correlation between the vasodilation response and PDE-5 inhibitory activity in the intact vessels was observed. Experimental protocol using the alpha-adrenergic (α1) receptor agonist, phenylephrine (PE), was undertaken to assess whether quinazoline derivatives showed competitive behavior similar to the α1 receptor blocker, prazosin, itself a quinazoline derivative, or to the PDE-5 inhibitor, sildenafil. Competitive experiments with the α1-adrenergic receptor agonist point to quinazoline derivatives under investigation here act via PDE-5 inhibition and not the former. The pre-incubation of pulmonary arterial rings with quinazoline test compounds (10 μM) reduced the contractile response to PE around 40–60%. The most promising compound (9) possessed ~32 folds higher selectivity in terms of vasodilation to its mammalian A549 cell cytotoxicity. This study provides experi0 0mental basis for PDE-5 inhibition as the mode of action for vasodilation by N2,N4-diamino quinazoline analogues along with their safety studies that may be beneficial in the treatment of various cardiovascular pathologies.

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Section: Discussionsupporting

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Elucidation of Vasodilation Response and Structure Activity Relationships of N2,N4-Disubstituted Quinazoline 2,4-Diamines in a Rat Pulmonary Artery Model

et al. 2019

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“…[24] The substitution of intermediate 18 with amine and then deprotection with TFA to provide the desirable compounds (for B1-3 and B7-12, the deprotection was not required). [25,26] 2.2 | Biology…”

Section: Chemistrymentioning

confidence: 99%

Discovery of 2,4‐diaminopyrimidine derivatives targeting p21‐activated kinase 4: Biological evaluation and docking studies

Qin

Yin

et al. 2020

Archiv der Pharmazie

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In this study, novel 2,4-diaminopyrimidine derivatives targeting p21-activated kinase 4 (PAK4) were discovered and evaluated for their biological activity against PAK4. Among the derivatives studied, promising compounds A2, B6, and B8 displayed the highest inhibitory activities against PAK4 (IC 50 = 18.4, 5.9, and 20.4 nM, respectively). From the cellular assay, compound B6 exhibited the highest potency with an IC 50 value of 2.533 μM against A549 cells. Some compounds were selected for computational ADME (absorption, distribution, metabolism, and elimination) properties and molecular docking studies against PAK4. The detailed structure-activity relationship based on the biochemical activities and molecular docking studies were explored. According to the docking studies, compound B6 had the lowest docking score (docking energy: −7.593 kcal/mol). The molecular docking simulation indicated the binding mode between compound B6 and PAK4. All these results suggest compound B6 as a useful candidate for the development of a PAK4 inhibitor.

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Computational design, synthesis and biological evaluation of PDE5 inhibitors based on N2,N4-diaminoquinazoline and N2,N6-diaminopurine scaffolds

Somnarin¹,

Pobsuk²,

Chantakul³

et al. 2022

Bioorganic & Medicinal Chemistry

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Design, synthesis and evaluation of N2,N4-diaminoquinazoline based inhibitors of phosphodiesterase type 5

Cited by 11 publications

References 29 publications

Elucidation of Vasodilation Response and Structure Activity Relationships of N2,N4-Disubstituted Quinazoline 2,4-Diamines in a Rat Pulmonary Artery Model

Elucidation of Vasodilation Response and Structure Activity Relationships of N2,N4-Disubstituted Quinazoline 2,4-Diamines in a Rat Pulmonary Artery Model

Discovery of 2,4‐diaminopyrimidine derivatives targeting p21‐activated kinase 4: Biological evaluation and docking studies

Computational design, synthesis and biological evaluation of PDE5 inhibitors based on N2,N4-diaminoquinazoline and N2,N6-diaminopurine scaffolds

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