Doherty A M, Kaltenbronn J S, Hudspeth J P, Repine J T, Roark W H, Sircar I, Tinney F J, Connolly C J, Hodges J C, Taylor M D
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
J Med Chem. 1991 Apr;34(4):1258-71. doi: 10.1021/jm00108a004.
A series of renin inhibitors with novel modifications at the P2 site has been prepared. Structure-activity relationships reveal that for a particular P2 fragment the in vitro potency is highly dependent on the nature of the P2' portion in addition to the P1-P1' group. The length of the P2 side chain and choice of epsilon-N P2 substitution have been found to be important for in vitro potency although the degree of unsaturation in the P2 side chain is not particularly significant. Molecular modeling studies have shown that it is possible for the P2 side chain to interact unfavorably with the P2' binding site. It has been possible to control the specificity for renin over cathepsin D by correct modification at the P2' and P1-P1' sites. Variations at the P4 site have been utilized to lower the log P values of these renin inhibitors while maintaining high potency. Compound 42, which exhibited an IC50 of 3.70 nM, log P of 2.3, and showed high specificity for renin, was selected for further studies. It was found to be very stable under neutral, acidic, and basic conditions. In simulated intestinal juice, compound 42 had a half-life of 37 min while it was virtually unaffected by simulated gastric juice after 4 h. Compound 42 produced a significant hypotensive response upon intravenous administration to the salt-depleted normotensive cynomolgus monkey.
已制备了一系列在P2位点具有新型修饰的肾素抑制剂。构效关系表明，对于特定的P2片段，除了P1-P1'基团外，体外活性高度依赖于P2'部分的性质。已发现P2侧链的长度和ε-N P2取代基的选择对体外活性很重要，尽管P2侧链的不饱和度程度不是特别显著。分子模拟研究表明，P2侧链有可能与P2'结合位点发生不利相互作用。通过在P2'和P1-P1'位点进行正确修饰，可以控制肾素相对于组织蛋白酶D的特异性。已利用P4位点的变化来降低这些肾素抑制剂的log P值，同时保持高效活性。选择表现出IC50为3.70 nM、log P为2.3且对肾素具有高特异性的化合物42进行进一步研究。发现它在中性、酸性和碱性条件下非常稳定。在模拟肠液中，化合物42的半衰期为37分钟，而在4小时后几乎不受模拟胃液的影响。化合物42静脉注射给低盐正常血压食蟹猴后产生了显著的降压反应。
