Jadhav P K, Ala P, Woerner F J, Chang C H, Garber S S, Anton E D, Bacheler L T
DuPont Merck Research Laboratories, DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880, USA.
J Med Chem. 1997 Jan 17;40(2):181-91. doi: 10.1021/jm960586t.
Cyclic urea amides, a novel series of HIV-1 protease (HIV PR) inhibitors, have increased activity against drug-resistant mutants of the HIV PR. The design strategy for these inhibitors is based on the hypotheses that (i) the hydrogen-bonding interactions between the inhibitor and the protease backbone will remain constant for wild-type and mutant enzymes and (ii) inhibitors which are capable of forming many nonbonded interactions, distributed throughout the active site, will experience a lower percent change in binding energy as a result of mutation in the target enzyme than those that form fewer interactions by partial occupation of the active site. The cyclic urea amide, SD146, forms 14 hydrogen bonds and 191 van der Waals contacts to HIV PR. SD146 is a very potent antiviral agent (IC90 = 5.1 nM) against wild-type HIV and maintains the same or improved level of high potency against a range of mutant strains of HIV with resistance to a wide variety of HIV protease inhibitors.
环脲酰胺是一类新型的HIV-1蛋白酶（HIV PR）抑制剂，对HIV PR的耐药突变体具有增强的活性。这些抑制剂的设计策略基于以下假设：（i）抑制剂与蛋白酶主链之间的氢键相互作用对于野生型和突变型酶将保持不变；（ii）能够在整个活性位点形成许多非键相互作用的抑制剂，由于靶酶中的突变，其结合能的变化百分比将低于那些通过部分占据活性位点而形成较少相互作用的抑制剂。环脲酰胺SD146与HIV PR形成14个氢键和191个范德华接触。SD146是一种针对野生型HIV的非常有效的抗病毒剂（IC90 = 5.1 nM），并且对一系列对多种HIV蛋白酶抑制剂具有抗性的HIV突变株保持相同或更高水平的高效能。
