Prasad J V, Boyer F E, Domagala J M, Ellsworth E L, Gajda C, Hamilton H W, Hagen S E, Markoski L J, Steinbaugh B A, Tait B D, Humblet C, Lunney E A, Pavlovsky A, Rubin J R, Ferguson D, Graham N, Holler T, Hupe D, Nouhan C, Tummino P J, Urumov A, Zeikus E, Zeikus G, Gracheck S J, Erickson J W
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Bioorg Med Chem. 1999 Dec;7(12):2775-800. doi: 10.1016/s0968-0896(99)00215-1.
With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices. The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfa nyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of > 1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. Cmax and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation.
基于与HIV蛋白酶结合的各种5,6-二氢吡喃-2-酮的X射线晶体结构所产生的见解，合成了在5,6-二氢吡喃-2-酮环的6位具有各种烷基的抑制剂。与6-苯基类似物相比，具有6-烷基的抑制剂表现出优异的抗病毒活性。当在苯乙基部分的4位引入极性基团（羟基或氨基）以及在3-（叔丁基-5-甲基-苯硫基）部分引入极性基团（羟甲基）时，抗病毒效力进一步提高。极性取代对于降低毒性也有利，为抑制剂提供了更高的治疗指数。该系列中最佳的抑制剂，(S)-6-[2-(4-氨基苯基)-乙基]-(3-(2-叔丁基-5-甲基-苯硫基)-4-羟基-6-异丙基-5,6-二氢-吡喃-2-酮（34S），表现出200 nM的EC50，治疗指数>1000。更重要的是，这些非肽类抑制剂16S和34S似乎对目前上市的拟肽类蛋白酶抑制剂几乎没有交叉抗性。在体外针对突变型HIV蛋白酶测试的所选抑制剂相对于野生型HIV蛋白酶显示出结合亲和力的非常小的增加。与16S相比，34S的Cmax和绝对生物利用度更高，半衰期和高于EC95的时间更长。因此，34S，也称为PD 178390，因其显示出良好的抗病毒效力、有前景的药代动力学特征以及对突变酶和CYP3A4的有利活性，已被选择进行进一步的临床前评估。
