Dorsey B D, Levin R B, McDaniel S L, Vacca J P, Guare J P, Darke P L, Zugay J A, Emini E A, Schleif W A, Quintero J C
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
J Med Chem. 1994 Oct 14;37(21):3443-51. doi: 10.1021/jm00047a001.
A series of HIV protease inhibitors possessing a hydroxylaminepentanamide transition state isostere have been developed. Incorporation of a basic amine into the backbone of the L-685,434 (2) series provided antiviral potency combined with a highly improved pharmacokinetic profile in animal models. Guided by molecular modeling and an X-ray crystal structure of the inhibited enzyme complex, we were able to design L-735,524. This compound is potent and competitively inhibits HIV-1 PR and HIV-2 PR with Ki values of 0.52 and 3.3 nM, respectively. It also stops the spread of the HIV-1IIIb-infected MT4 lymphoid cells at concentrations of 25-50 nM. To date, numerous HIV-PR inhibitors have been reported, but few have been studied in humans because they lack acceptable oral bioavailability. L-735,524 is orally bioavailable in three animals models, using clinically acceptable formulations, and is currently in phase II human clinical trials.
一系列具有羟胺戊酰胺过渡态类似物的HIV蛋白酶抑制剂已被开发出来。将碱性胺引入L-685,434（2）系列的主链中，在动物模型中提供了抗病毒效力并结合了高度改善的药代动力学特征。在分子建模和被抑制的酶复合物的X射线晶体结构的指导下，我们能够设计出L-735,524。该化合物具有强效，分别以0.52和3.3 nM的Ki值竞争性抑制HIV-1 PR和HIV-2 PR。它还能在25 - 50 nM的浓度下阻止HIV-1IIIb感染的MT4淋巴细胞的扩散。迄今为止，已报道了许多HIV-PR抑制剂，但由于缺乏可接受的口服生物利用度，很少有在人体中进行研究的。L-735,524在三种动物模型中具有口服生物利用度，使用临床上可接受的制剂，目前正处于II期人体临床试验阶段。
