BACKGROUND: Recent clinical trials have demonstrated that HIV protease inhibitors are useful in the treatment of AIDS. It is necessary, however, to use HIV protease inhibitors in combination with other antiviral agents to inhibit the development of resistance. The daunting ability of the virus to rapidly generate resistant mutants suggests that there is an ongoing need for new HIV protease inhibitors with superior pharmacokinetic and efficacy profiles. In our attempts to design and select improved cyclic urea HIV protease inhibitors, we have simultaneously optimized potency, resistance profile, protein binding and oral bioavailability. RESULTS: We have discovered that nonsymmetrical cyclic ureas containing a 3-aminoindazole P2 group are potent inhibitors of HIV protease with excellent oral bioavailability. Furthermore, the 3-aminoindazole group forms four hydrogen bonds with the enzyme and imparts a good resistance profile. The nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851 were selected as our next generation of cyclic urea HIV protease inhibitors because they achieve 8 h trough blood levels in dog, with a 10 mg/kg dose, at or above the protein-binding-adjusted IC90 value for the worst single mutant--that containing the Ile84-->Val mutation. CONCLUSIONS: In selecting our next generation of cyclic urea HIV protease inhibitors, we established a rigorous set of criteria designed to maximize chances for a sustained antiviral effect in HIV-infected individuals. As DMP 850 and DMP 851 provide plasma levels of free drug that are sufficient to inhibit wild-type HIV and several mutant forms of HIV, they could show improved ability to decrease viral load for clinically significant time periods. The ultimate success of DMP 850 and DMP 851 in clinical trials might depend on achieving or exceeding the oral bioavailability seen in dog.

中文翻译：

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DMP 850和DMP 851的设计和选择：下一代环状尿素HIV蛋白酶抑制剂。

背景技术：最近的临床试验表明，HIV蛋白酶抑制剂可用于治疗艾滋病。但是，有必要将HIV蛋白酶抑制剂与其他抗病毒剂联合使用以抑制耐药性的发展。病毒快速产生抗性突变体的艰巨能力表明，目前仍需要具有优异药代动力学和功效特征的新型HIV蛋白酶抑制剂。在我们设计和选择改良的环状尿素HIV蛋白酶抑制剂的尝试中，我们同时优化了效价，耐药性，蛋白质结合和口服生物利用度。结果：我们发现包含3-氨基吲唑P2基团的非对称环状脲是有效的HIV蛋白酶抑制剂，口服生物利用度极佳。此外，3-氨基吲唑基团与酶形成四个氢键并具有良好的抗性。选择非对称的3-氨基吲唑DMP 850和DMP 851作为我们的下一代环状尿素HIV蛋白酶抑制剂，因为它们以10 mg / kg的剂量达到或超过蛋白质结合调节后的狗血中8 h谷浓度最坏的单个突变体（包含Ile84）>> Val突变的IC90值。结论：在选择我们的下一代环脲HIV蛋白酶抑制剂时，我们建立了一套严格的标准，旨在最大程度地提高在HIV感染者中持续产生抗病毒作用的机会。由于DMP 850和DMP 851提供的血浆游离药物水平足以抑制野生型HIV和几种突变形式的HIV，在临床上重要的时间段内，它们可以显示出降低病毒载量的增强能力。DMP 850和DMP 851在临床试验中的最终成功可能取决于达到或超过狗的口服生物利用度。