RESUMEN

The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic HIV-1 protease inhibitors with rationally designed P2' ligands are described. The inhibitors are designed to enhance backbone binding interactions, particularly at the S2' subsite. Synthesis of inhibitors was carried out efficiently. The stereochemistry of alcohol functionalities of the P2' ligands was set by asymmetric reduction of the corresponding ketone using (R,R)- or (S,S)-Noyori catalysts. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 3g and 3h showed enzyme Ki values of 27.9 and 49.7 pm and antiviral activity of 6.2 and 3.9 nm, respectively. These inhibitors also remained quite potent against darunavir-resistant HIV-1 variants. An X-ray structure of inhibitor 3g in complex with HIV-1 protease revealed key interactions in the S2' subsite.

Asunto(s)

Darunavir/farmacología , Diseño de Fármacos , Inhibidores de la Proteasa del VIH/farmacología , Proteasa del VIH/metabolismo , Cristalografía por Rayos X , Darunavir/síntesis química , Darunavir/química , Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/química , Ligandos , Modelos Moleculares , Conformación Molecular , Relación Estructura-Actividad

RESUMEN

Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (Ki=13.2nM, IC50=22nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (Ki=62pM and 14pM, respectively) and antiviral activity (IC50=5.3nM and 2.0nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.

Asunto(s)

Diseño de Fármacos , Inhibidores de la Proteasa del VIH/síntesis química , Proteasa del VIH/metabolismo , Compuestos Macrocíclicos/química , Sitios de Unión , Cristalografía por Rayos X , Proteasa del VIH/química , Proteasa del VIH/genética , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/metabolismo , VIH-1/enzimología , Concentración 50 Inhibidora , Ligandos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/metabolismo , Simulación de Dinámica Molecular , Mutación , Estructura Terciaria de Proteína , Pirrolidinonas/química , Relación Estructura-Actividad

RESUMEN

Design, synthesis, biological and X-ray crystallographic studies of a series of potent HIV-1 protease inhibitors are described. Various polar functionalities have been incorporated on the tetrahydropyranyl-tetrahydrofuran-derived P2 ligand to interact with the backbone atoms in the S2-subsite. The majority of the inhibitors showed very potent enzyme inhibitory and antiviral activity. Two high-resolution X-ray structures of 30b- and 30j-bound HIV-1 protease provide insight into ligand-binding site interactions. In particular, the polar functionalities on the P2-ligand appear to form unique hydrogen bonds with Gly48 amide NH and amide carbonyl groups in the flap region.

Asunto(s)

Amidas/química , Diseño de Fármacos , Furanos/química , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , Piranos/química , Amidas/farmacología , Cristalografía por Rayos X , Inhibidores de la Proteasa del VIH/síntesis química , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Ligandos , Estructura Molecular

RESUMEN

GRL007 and GRL008, two structurally related nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF) as the P2 moiety and a sulfonamide isostere consisting of benzene carboxylic acid and benzene carboxamide as the P2' moiety, respectively, were evaluated for their antiviral activity and interactions with wild-type protease (PR(WT)). Both GRL007 (Ki of 12.7 pM with PR(WT)) and GRL008 (Ki of 8.9 pM) inhibited PR(WT) with high potency in vitro. X-ray crystallographic analysis of PR(WT) in complex with GRL007 or GRL008 showed that the bis-THF moiety of both compounds has three direct polar contacts with the backbone amide nitrogen atoms of Asp29 and Asp30 of PR(WT). The P2' moiety of both compounds showed one direct contact with the backbone of Asp30' and a bridging polar contact with Gly48' through a water molecule. Cell-based antiviral assays showed that GRL007 was inactive (50% effective concentration [EC50] of >1 µM) while GRL008 was highly active (EC50 of 0.04 µM) against wild-type HIV-1. High-performance liquid chromatography (HPLC)/mass spectrometry-based cellular uptake assays showed 8.1- and 84-fold higher intracellular concentrations of GRL008 than GRL007 in human MT-2 and MT-4 cell extracts, respectively. Thus, GRL007, in spite of its favorable enzyme-inhibitory activity and protease binding profile, exhibited a lack of antiviral activity in cell-based assays, most likely due to its compromised cellular uptake associated with its P2' benzene carboxylic acid moiety. The anti-HIV-1 potency, favorable toxicity, and binding profile of GRL008 suggest that further optimization of the P2' moiety may improve its antiretroviral features.

Asunto(s)

Benceno/química , Benzoatos/química , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , Proteasa del VIH/química , Indoles/química , Dominio Catalítico , Línea Celular , Cromatografía Líquida de Alta Presión , Humanos , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad , Difracción de Rayos X

RESUMEN

The design, synthesis, and biological evaluation of novel C3-substituted cyclopentyltetrahydrofuranyl (Cp-THF)-derived HIV-1 protease inhibitors are described. Various C3-functional groups on the Cp-THF ligand were investigated in order to maximize the ligand-binding site interactions in the flap region of the protease. Inhibitors 3c and 3d have displayed the most potent enzyme inhibitory and antiviral activity. Both inhibitors have maintained impressive activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 3c-bound HIV-1 protease revealed a number of important molecular insights into the ligand-binding site interactions.

Asunto(s)

Ciclopentanos/síntesis química , Furanos/síntesis química , Inhibidores de la Proteasa del VIH/síntesis química , Proteasa del VIH/metabolismo , Uretano/análogos & derivados , Uretano/síntesis química , Sitios de Unión , Cristalografía por Rayos X , Ciclopentanos/farmacología , Darunavir , Diseño de Fármacos , Farmacorresistencia Viral/efectos de los fármacos , Furanos/farmacología , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/enzimología , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/virología , Modelos Moleculares , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacología , Uretano/farmacología

RESUMEN

We report the design, synthesis, biological evaluation, and the X-ray crystal structure of a novel inhibitor bound to the HIV-1 protease. Various C3-functionalized cyclopentanyltetrahydrofurans (Cp-THF) were designed to interact with the flap Gly48 carbonyl or amide NH in the S2-subsite of the HIV-1 protease. We investigated the potential of those functionalized ligands in combination with hydroxyethylsulfonamide isosteres. Inhibitor 26 containing a 3-(R)-hydroxyl group on the Cp-THF core displayed the most potent enzyme inhibitory and antiviral activity. Our studies revealed a preference for the 3-(R)-configuration over the corresponding 3-(S)-derivative. Inhibitor 26 exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray structure of 26-bound HIV-1 protease revealed important molecular insight into the ligand-binding site interactions.

Asunto(s)

Diseño de Fármacos , Inhibidores de la Proteasa del VIH/metabolismo , Proteasa del VIH/metabolismo , Ligandos , Uretano/metabolismo , Sustitución de Aminoácidos , Sitios de Unión , Biocatálisis/efectos de los fármacos , Línea Celular , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Proteasa del VIH/química , Proteasa del VIH/genética , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/enzimología , VIH-1/genética , Humanos , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Mutación , Unión Proteica , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Uretano/química , Uretano/farmacología

RESUMEN

The design, synthesis, and evaluation of a new series of hexahydrofuropyranol-derived HIV-1 protease inhibitors are described. We have designed a stereochemically defined hexahydrofuropyranol-derived urethane as the P2-ligand. The current ligand is designed based upon the X-ray structure of 1a-bound HIV-1 protease. The synthesis of (3aS,4S,7aR)-hexahydro-2H-furo[2,3-b]pyran-4-ol, (-)-7, was carried out in optically active form. Incorporation of this ligand provided inhibitor 35a, which has shown excellent enzyme inhibitory activity and antiviral potency. Our structure-activity studies have indicated that the stereochemistry and the position of oxygens in the ligand are important to the observed potency of the inhibitor. Inhibitor 35a has maintained excellent potency against multidrug-resistant HIV-1 variants. An active site model of 35a was created based upon the X-ray structure of 1b-bound HIV-1 protease. The model offers molecular insights regarding ligand-binding site interactions of the hexahydrofuropyranol-derived novel P2-ligand.

Asunto(s)

Carbamatos/síntesis química , Inhibidores de la Proteasa del VIH/síntesis química , Proteasa del VIH/metabolismo , VIH-1/efectos de los fármacos , Modelos Moleculares , Sulfonamidas/síntesis química , Carbamatos/química , Carbamatos/farmacología , Dominio Catalítico , Línea Celular , Cristalografía por Rayos X , Farmacorresistencia Viral Múltiple , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/aislamiento & purificación , Humanos , Ligandos , Unión Proteica , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología

RESUMEN

We investigated substituted bis-THF-derived HIV-1 protease inhibitors in order to enhance ligand-binding site interactions in the HIV-1 protease active site. In this context, we have carried out convenient syntheses of optically active bis-THF and C4-substituted bis-THF ligands using a [2,3]-sigmatropic rearrangement as the key step. The synthesis provided convenient access to a number of substituted bis-THF derivatives. Incorporation of these ligands led to a series of potent HIV-1 protease inhibitors. Inhibitor 23c turned out to be the most potent (K(i) = 2.9 pM; IC(50) = 2.4 nM) among the inhibitors. An X-ray structure of 23c-bound HIV-1 protease showed extensive interactions of the inhibitor with the protease active site, including a unique water-mediated hydrogen bond to the Gly-48 amide NH in the S2 site.