In light of accumulating evidence that aggressive LDL-lowering therapy may offer increased protection against coronary heart disease, we undertook the design and synthesis of a novel series of HMG-CoA reductase inhibitors based upon a substituted pyrazole template. Optimizing this series using both structure-based design and molecular property considerations afforded a class of highly efficacious and hepatoselective inhibitors resulting in the identification of (3 R,5 R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2 H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic (PF-3052334) as a candidate for the treatment of hypercholesterolemia.

中文翻译：

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取代的吡唑类药物作为肝选择性HMG-CoA还原酶抑制剂：发现（3R，5R）-7- [2-（4-氟-苯基）-4-异丙基-5-（4-甲基-苄基氨基甲酰基）-2H-吡唑I- 3-基] -3,5-二羟基庚酸（PF-3052334）作为治疗高胆固醇血症的候选药物。

鉴于越来越多的证据表明降低LDL的积极治疗可能会增强抵抗冠心病的保护作用，我们基于取代的吡唑模板进行了一系列新型HMG-CoA还原酶抑制剂的设计和合成。使用基于结构的设计和分子特性的考虑来优化该系列，可提供一类高效且具有肝选择性的抑制剂，从而可鉴定出（3 R，5 R）-7- [2-（4-氟-苯基）-4-异丙基-5-（4-甲基-苄基氨基甲酰基）-2 H-吡唑-3-基] -3,5-二羟基庚酸（PF-3052334）作为治疗高胆固醇血症的候选药物。