L-735,524 - THE DESIGN OF A POTENT AND ORALLY BIOAVAILABLE HIV PROTEASE INHIBITOR
L-735,524 - THE DESIGN OF A POTENT AND ORALLY BIOAVAILABLE HIV PROTEASE INHIBITOR
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DOI：
10.1021/jm00047a001
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发表时间：
1994-10-14
影响因子：
7.3
通讯作者：
HUFF, JR
中科院分区：
文献类型：
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作者：
DORSEY, BD;LEVIN, RB;HUFF, JR
已经开发了一系列具有羟胺戊酰胺过渡态电子等排体的HIV蛋白酶抑制剂。在L-685，434（2）系列的骨架中加入碱性胺，可提供抗病毒效力，并在动物模型中高度改善药代动力学特征。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L-735，524。该化合物是有效的，竞争性抑制HIV-1 PR和HIV-2 PR，Ki值分别为0.52和3.3 nM。它还可以在25-50 nM的浓度下阻止HIV-1（IIIb）感染的MT4淋巴细胞的扩散。迄今为止，已经报道了许多HIV-PR抑制剂，但很少在人类中进行研究，因为它们缺乏可接受的口服生物利用度。L-735，524在三种动物模型中具有口服生物利用度，使用临床可接受的制剂，目前处于II期人体临床试验中。
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 K-i values of 0.52 and 3.3 nM, respectively. It also stops the spread of the HIV-1(IIIb)-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.