Pace Paola, Di Francesco M Emilia, Gardelli Cristina, Harper Steven, Muraglia Ester, Nizi Emanuela, Orvieto Federica, Petrocchi Alessia, Poma Marco, Rowley Michael, Scarpelli Rita, Laufer Ralph, Gonzalez Paz Odalys, Monteagudo Edith, Bonelli Fabio, Hazuda Daria, Stillmock Kara A, Summa Vincenzo
Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti S.p.A. (Merck Research Laboratories, Rome), Via Pontina Km 30,600, 00040 Pomezia, Italy.
J Med Chem. 2007 May 3;50(9):2225-39. doi: 10.1021/jm070027u. Epub 2007 Apr 12.
Human immunodeficiency virus type-1 (HIV-1) integrase, one of the three constitutive viral enzymes required for replication, is a rational target for chemotherapeutic intervention in the treatment of AIDS that has also recently been confirmed in the clinical setting. We report here on the design and synthesis of N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides as a class of agents which exhibits potent inhibition of the HIV-integrase-catalyzed strand transfer process. In the current study, structural modifications on these molecules were made in order to examine effects on HIV-integrase inhibitory potencies. One of the most interesting compounds for this series is 2-[1-(dimethylamino)-1-methylethyl]-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide 38, with a CIC95 of 78 nM in the cell-based assay in the presence of serum proteins. The compound has favorable pharmacokinetic properties in preclinical species (rats, dogs, and monkeys) and shows no liabilities in several counterscreening assays, highlighting its potential as a clinically useful antiviral agent.
人类免疫缺陷病毒1型（HIV-1）整合酶是病毒复制所需的三种组成性酶之一，是艾滋病化疗干预的合理靶点，最近在临床环境中也得到了证实。我们在此报告N-苄基-5,6-二羟基嘧啶-4-甲酰胺类药物的设计与合成，这类药物对HIV整合酶催化的链转移过程具有强效抑制作用。在当前研究中，对这些分子进行了结构修饰，以考察其对HIV整合酶抑制效力的影响。该系列中最有趣的化合物之一是2-[1-(二甲氨基)-1-甲基乙基]-N-(4-氟苄基)-5,6-二羟基嘧啶-4-甲酰胺38，在有血清蛋白存在的细胞实验中，其半数抑制浓度（CIC95）为78 nM。该化合物在临床前物种（大鼠、狗和猴子）中具有良好的药代动力学性质，并且在多项筛选实验中未显示出不良反应，突出了其作为临床可用抗病毒药物的潜力。
