De Lucca G V, Kim U T, Liang J, Cordova B, Klabe R M, Garber S, Bacheler L T, Lam G N, Wright M R, Logue K A, Erickson-Viitanen S, Ko S S, Trainor G L
Dupont Merck Pharmaceutical Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.
J Med Chem. 1998 Jun 18;41(13):2411-23. doi: 10.1021/jm980103g.
Using the structural information gathered from the X-ray structures of various cyclic urea/HIVPR complexes, we designed and synthesized many nonsymmetrical P2/P2'-substituted cyclic urea analogues. Our efforts concentrated on using an indazole as one of the P2 substituents since this group imparted enzyme (Ki) potency as well as translation into excellent antiviral (IC90) potency. The second P2 substituent was used to adjust the physical and chemical properties in order to maximize oral bioavailability. Using this approach several very potent (IC90 11 nM) and orally bioavailable (F% 93-100%) compounds were discovered (21, 22). However, the resistance profiles of these compounds were inadequate, especially against the double (I84V/V82F) and ritonavir-selected mutant viruses. Further modification of the second P2 substituent in order to increase H-bonding interactions with the backbone atoms of residues Asp 29, Asp 30, and Gly 48 led to analogues with much better resistance profiles. However, these larger analogues were incompatible with the apparent molecular weight requirements for good oral bioavailability of the cyclic urea class of HIVPR inhibitors (MW < 610).
利用从各种环脲/HIV蛋白酶复合物的X射线结构中收集到的结构信息，我们设计并合成了许多非对称的P2/P2'-取代环脲类似物。我们的工作重点是使用吲唑作为P2取代基之一，因为该基团赋予了酶（Ki）活性以及出色的抗病毒（IC90）活性。第二个P2取代基用于调节物理和化学性质，以最大化口服生物利用度。通过这种方法发现了几种非常有效的（IC90为11 nM）且具有口服生物利用度的（F%为93 - 100%）化合物（21、22）。然而，这些化合物的耐药谱并不理想，尤其是对双突变（I84V/V82F）和利托那韦选择的突变病毒。对第二个P2取代基进行进一步修饰，以增加与天冬氨酸29、天冬氨酸30和甘氨酸48残基主链原子的氢键相互作用，从而得到了耐药谱更好的类似物。然而，这些较大的类似物不符合环脲类HIV蛋白酶抑制剂良好口服生物利用度的表观分子量要求（MW < 610）。
