作为强效和选择性磷酸二酯酶5（PDE5）抑制剂的氨基取代吡啶并[3,2 - b]吡嗪酮的鉴定、合成及构效关系研究

Identification, synthesis and SAR of amino substituted pyrido[3,2b]pyrazinones as potent and selective PDE5 inhibitors.

作者信息

Owen Dafydd R, Walker John K, Jon Jacobsen E, Freskos John N, Hughes Robert O, Brown David L, Bell Andrew S, Brown David G, Phillips Christopher, Mischke Brent V, Molyneaux John M, Fobian Yvette M, Heasley Steve E, Moon Joseph B, Stallings William C, Joseph Rogier D, Fox David N A, Palmer Michael J, Ringer Tracy, Rodriquez-Lens Margarita, Cubbage Jerry W, Blevis-Bal Radhika M, Benson Alan G, Acker Brad A, Maddux Todd M, Tollefson Michael B, Bond Brian R, Macinnes Alan, Yu Yung

机构信息

Department of Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.

出版信息

Bioorg Med Chem Lett. 2009 Aug 1;19(15):4088-91. doi: 10.1016/j.bmcl.2009.06.012. Epub 2009 Jun 6.

DOI:10.1016/j.bmcl.2009.06.012

PMID:19540112

Abstract

A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.

摘要

公开了一类新型的强效且选择性的磷酸二酯酶5（PDE5）抑制剂。在X射线晶体学数据的指导下，对高通量筛选（HTS）先导化合物进行优化，从而发现了一系列2-芳基、（N8）-烷基取代的-6-氨基取代的吡啶并[3,2-b]吡嗪酮，这些化合物对PDE5酶表现出强效抑制作用。文中还给出了合成细节以及一些构效关系。