Novel benzophenones as non-nucleoside reverse transcriptase inhibitors of HIV-1

GW4511, GW4751, and GW3011 showed IC50 values < or =2 nM against wild type HIV-1 and <10 nM against 16 mutants. They were particularly potent against NNRTI-resistant viruses containing Y181C-, K103N-, and K103N-based double mutations, which account for a significant proportion of the clinical failure of the three currently marketed NNRTIs. The antiviral data together with the favorable pharmacokinetic data of GW4511 suggested that these benzophenones possess attributes of a new NNRTI drug candidate.     

二芳基胺类HIV-1非核苷类逆转录酶抑制剂研究进展

开发新型具有高效抗耐药性及良好药动学性质的非核苷类逆转录酶抑制剂（NNRTIs）依然是目前抗艾滋病药物研究领域迫切需要解决的科研问题。NNRTIs呈现结构多样性,但是其药效团却具有很大的相似性,不同类型的NNRTIs分子中往往存在共同或相近的骨架体系——优势结构。近年来被广泛研究的二芳基嘧啶类、二苯基唑类和“杂环-NH-取代苯”类NNRTIs分子中均存在二芳基胺（U—Het—NH-PhX）这一优势结构,虽然这3类抑制剂研发过程不同,但它们的研发历程对以优势结构为导向的NNRTIs骨架变换及取代基优化具有重要的指导意义。本文综述了含有二芳基胺优势结构的NNRTIs的研究进展。     

HIV非核苷类逆转录酶抑制剂研究进展

1引言艾滋病(AIDS)是由人类免疫缺陷病毒(HIV)感染引起的严重疾病。HIV属于RNA逆转录病毒,又分为HIV 1和HIV 2型。这两种类型病毒的基因组在DNA碱基序列方面有着明显的差别,因而相应的逆转录酶和包膜上糖蛋白的结构有所不同。世界上大部分地区的艾滋病人是被病毒HIV 1所感染,现     

Design and synthesis of conformationally constrained inhibitors of non-nucleoside reverse transcriptase

Highly active antiretroviral therapy (HAART) significantly reduces human immunodeficiency virus (HIV) viral load and has led to a dramatic decrease in acquired immunodeficiency syndrome (AIDS) related mortality. Despite this success, there remains a critical need for new HIV therapies to address the emergence of drug resistant viral strains. Next generation NNRTIs are sought that are effective against these mutant forms of the HIV virus. The bound conformations of our lead inhibitors, MK-1107 (1) and MK-4965 (2), were divergent about the oxymethylene linker, and each of these conformations was rigidified using two isomeric cyclic constraints. The constraint derived from the bioactive conformation of 2provided novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Systematic SAR led to the identification of indazole as the optimal conformational constraint to provide MK-6186 (3) and MK-7445 (6). Despite their reduced flexibility, these compounds had potency comparable to that of the corresponding acyclic ethers in both recombinant enzyme and cell based assays against both the wild-type and the clinically relevant mutant strains.     

The QSAR analysis of tricyclic non-nucleoside inhibitors of HIV-1 reverse transcriptase

The inhibitory activities against HIV-1 RT of 44 tricyclic oxazepinones (from ref. 8, 9, 12) and 76 tricyclic diazepinones (from ref. 10, 11) have been correlated with 15 physicochemical parameters. The physicochemical parameters and 3D models of investigated compounds were obtained with the HyperChem program. A correlation between biological activity data (from ref. 8-12) and physicochemical data of the examined compounds was investigated by the regression analysis method with the STATISTICA program.     

Three-dimensional quantitative structure-activity relationships of inhibitors of P-glycoprotein

P-glycoprotein (P-gp) is an efflux transporter involved in limiting the oral bioavailability and tissue penetration of a variety of structurally divergent molecules. A better understanding of the structural requirements of modulators of P-gp function will aid in the design of therapeutic agents. Toward this goal, three-dimensional quantitative structure-activity relationship (3D-QSAR) models were generated using in vitro data associated with inhibition of P-gp function. Several approaches were undertaken with multiple iterations, yielding Catalyst 3D-QSAR models being able to qualitatively rank-order and predict IC(50) values for P-gp inhibitors excluded from the model in question. The success of these validations suggests that a P-gp pharmacophore for 27 inhibitors of digoxin transport in Caco-2 cells consisted of four hydrophobes and one hydrogen bond acceptor. A second pharmacophore generated with 21 inhibitors of vinblastine binding to plasma membrane vesicles derived from CEM/VLB(100) cells contained three ring aromatic features and one hydrophobic feature. A third pharmacophore generated with 17 inhibitors of vinblastine accumulation in P-gp expressing LLC-PK1 cells contained four hydrophobes and one hydrogen bond acceptor. A final pharmacophore was generated for inhibition of calcein accumulation in P-gp expressing LLC-PK1 cells and found to contain two hydrophobes, a ring aromatic feature, and a hydrogen bond donor. The similarity of features for the pharmacophores of P-gp inhibitors of digoxin transport and vinblastine binding suggest some commonality in their binding sites. Utilization of such models may prove to be of value for prediction of molecules that may modulate one or more P-gp binding sites.