Letourneau Jeffrey J, Liu Jinqi, Ohlmeyer Michael H J, Riviello Chris, Rong Yajing, Li Hong, Appell Kenneth C, Bansal Shalini, Jacob Biji, Wong Angela, Webb Maria L
Department of Chemistry, Pharmacopeia, Inc., PO Box 5350, Princeton, NJ 08543, USA.
Bioorg Med Chem Lett. 2009 Jan 15;19(2):352-5. doi: 10.1016/j.bmcl.2008.11.074. Epub 2008 Nov 24.
The discovery, synthesis and preliminary SAR of a novel class of non-peptidic antagonists of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5) is described. High-throughput screening of an extensive series of ECLiPStrade mark compound libraries led to the identification of compound 1 as a dual inhibitor of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5). Optimization of compound 1 involving, in part, introduction of two novel constraints led to the discovery of compounds 15a and 15b with reduced PSA and much improved potency for both the alpha(v)beta(3) and alpha(v)beta(5) integrins. Compounds 15a and 15b were shown to have promising activity in functional cellular assays and compound 15a also exhibited a promising Caco-2 permeability profile.
描述了一类新型α(v)整合素α(v)β(3)和α(v)β(5)的非肽类拮抗剂的发现、合成及初步构效关系。对一系列广泛的ECLiPS商标化合物库进行高通量筛选，确定化合物1为α(v)整合素α(v)β(3)和α(v)β(5)的双重抑制剂。对化合物1的优化，部分涉及引入两个新的限制条件，从而发现了化合物15a和15b，其PSA降低，对α(v)β(3)和α(v)β(5)整合素的效力有显著提高。化合物15a和15b在细胞功能试验中显示出有前景的活性，化合物15a还表现出有前景的Caco-2通透性特征。
