Ferrocenyl, Alkyl, and Aryl-Pyrido[2,3-d]Pyrimidines as Vasorelaxant of Smooth Muscle of Rat Aorta via cAMP Conservation Through Phosphodiesterase Inhibition

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• 作者：Ivonne Arellano ; Fernando Rodrí ; guez-Ramos ; Martí ; n Gonzá ; lez-Andrade ; André ; s Navarrete ; Manju Sharma ; Noé ; Rosas and Pankaj Sharma
• 刊名：Journal of Heterocyclic Chemistry
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：53
• 期：4
• 页码：1147-1154
• 全文大小：615K
• ISSN：1943-5193

文摘

New pyrido[2,3-d]pyrimidines ces:#jhet2380-eo-0011">, ces:#jhet2380-eo-0012">, ces:#jhet2380-eo-0013">, and ces:#jhet2380-eo-0021"> have been synthesized. The vasorelaxant effect on smooth muscle isolated from rat aorta, via PDEs inhibition, of these compounds along with other pyrido[2,3-d]pyrimidines ces:#jhet2380-eo-0014 #jhet2380-eo-0015 #jhet2380-eo-0016 #jhet2380-eo-0017 #jhet2380-eo-0018 #jhet2380-eo-0019 #jhet2380-eo-0020"> reported earlier by our group, has also been determined. These pyrido[2,3-d]pyrimidines ces:#jhet2380-eo-0011 #jhet2380-eo-0012 #jhet2380-eo-0013 #jhet2380-eo-0014 #jhet2380-eo-0015 #jhet2380-eo-0016 #jhet2380-eo-0017 #jhet2380-eo-0018 #jhet2380-eo-0019 #jhet2380-eo-0020 #jhet2380-eo-0021"> were synthesized by the reaction of ferrocenyl-ethynyl ketones (ces:#jhet2380-eo-0001 #jhet2380-eo-0002 #jhet2380-eo-0003 #jhet2380-eo-0004">) or α-alkynyl ketones (ces:#jhet2380-eo-0005 #jhet2380-eo-0006 #jhet2380-eo-0007 #jhet2380-eo-0008 #jhet2380-eo-0009 #jhet2380-eo-0010">) with com/namespaces/wiley" xmlns:cr="urn://wiley-online-library/content/render" xmlns:mml="http://www.w3.org/1998/Math/MathML" id="jhet2380-eo-2000">class="TH_term3">6-amino-1,3-dimethyluracil using [Ni(CN)₄]⁻⁴ as an active catalytic species, formed in situ in a Ni(CN)₂/NaOH/H₂O/CO/KCN aqueous system. Evaluation of the vasorelaxant effect of compounds ces:#jhet2380-eo-0011 #jhet2380-eo-0012 #jhet2380-eo-0013 #jhet2380-eo-0014 #jhet2380-eo-0015 #jhet2380-eo-0016 #jhet2380-eo-0017 #jhet2380-eo-0018 #jhet2380-eo-0019 #jhet2380-eo-0020 #jhet2380-eo-0021"> demonstrated that all compounds relax the tissue in a concentration-dependent manner. The structural changes do not alter the effectiveness; however, there are differences related to potency expressed as EC₅₀. Compounds ces:#jhet2380-eo-0012"> (7-ferrocenyl-1,3-dimethyl-5-(m-tolyl)-pyrido[2,3-d]pyrimidine) and ces:#jhet2380-eo-0013"> (7-ferrocenyl-1,3-dipropyl-5-(4-metoxyphenyl)-pyrido[2,3-d]pyrimidine) were the most potent compounds, even more than rolipram, reference drug; the EC₅₀ was 0.41 ± 0.02 μM and 0.81 ± 0.11 μM for ces:#jhet2380-eo-0012"> and ces:#jhet2380-eo-0013">, correspondingly. The EC₅₀ of compounds ces:#jhet2380-eo-0015"> (7-ferrocenyl-1,3-dimethyl-5-phenyl-pyrido[2,3-d]pyrimidine), ces:#jhet2380-eo-0014"> (7-ferrocenyl-5-(3,5-dimethoxyphenyl)-1,3-dimethylpyrido[2,3-d]pyrimidine), and ces:#jhet2380-eo-0019"> (5-n-butyl-7-ethyl-1,3-dimethylpyrido[2,3-d]pyrimidine) was similar to EC₅₀ of rolipram. Compounds ces:#jhet2380-eo-0011 #jhet2380-eo-0012 #jhet2380-eo-0013 #jhet2380-eo-0014 #jhet2380-eo-0015 #jhet2380-eo-0016 #jhet2380-eo-0017 #jhet2380-eo-0018 #jhet2380-eo-0019 #jhet2380-eo-0020 #jhet2380-eo-0021"> significantly induce concentration-dependent vasorelaxation in endothelium-intact aortic rings. In addition, the relaxation responses to each compound in either endothelium-intact or endothelium denuded aortic rings were comparable, suggesting that removal of the functional endothelium has no significant influence on its intrinsic vasorelaxant activity. In vitro capability of conserving cyclic-AMP or cyclic-GMP (adenosine and guanosine 3′, 5′-cyclic monophosphate) via PDE inhibition for compounds ces:#jhet2380-eo-0012 #jhet2380-eo-0013 #jhet2380-eo-0014 #jhet2380-eo-0015"> and ces:#jhet2380-eo-0019"> was evaluated. Compounds ces:#jhet2380-eo-0015"> and ces:#jhet2380-eo-0019"> show the highest percent inhibition effect (94.83% and 83.98%, respectively) for the decomposition of c-AMP. Docking studies showed that the compound ces:#jhet2380-eo-0015"> was selective for the inhibition of PDE-4.