RESUMEN
Optimization of pyridine-based noncatalytic site integrase inhibitors (NCINIs) based on compound 2 has led to the discovery of molecules capable of inhibiting virus harboring N124 variants of HIV integrase (IN) while maintaining minimal contribution of enterohepatic recirculation to clearance in rat. Structure-activity relationships at the C6 position established chemical space where the extent of enterohepatic recirculation in the rat is minimized. Desymmetrization of the C4 substituent allowed for potency optimization against virus having the N124 variant of integrase. Combination of these lessons led to the discovery of compound 20, having balanced serum-shifted antiviral potency and minimized excretion in to the biliary tract in rat, potentially representing a clinically viable starting point for a new treatment option for individuals infected with HIV.
RESUMEN
An assay recapitulating the 3' processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/aa125 variants of IN. The importance of the C7 position on the serum shifted potency was established. Introduction of a quinoline substituent at the C4 position provided a balance of potency and metabolic stability. Combination of these findings ultimately led to the discovery of compound 26 (BI 224436), the first NCINI to advance into a phase Ia clinical trial.
RESUMEN
The design and preliminary SAR of a new series of 1H-quinazolin-4-one (QAZ) allosteric HCV NS5B thumb pocket 2 (TP-2) inhibitors was recently reported. To support optimization efforts, a molecular dynamics (MD) based modeling workflow was implemented, providing information on QAZ binding interactions with NS5B. This approach predicted a small but critical ligand-binding induced movement of a protein backbone region which increases the pocket size and improves access to the backbone carbonyl groups of Val 494 and Pro 495. This localized backbone shift was consistent with key SAR results and was subsequently confirmed by X-ray crystallography. The MD protocol guided the design of inhibitors, exploiting novel H-bond interactions with the two backbone carbonyl groups, leading to the first thumb pocket 2 NS5B inhibitor with picomolar antiviral potency in genotype (gt) 1a and 1b replicons (EC50 = 120 and 110 pM, respectively) and with EC50 ≤ 80 nM against gt 2-6.
Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Replicón/efectos de los fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Regulación Alostérica , Antivirales/química , Línea Celular , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Hepacivirus/genética , Simulación de Dinámica Molecular , Relación Estructura-ActividadRESUMEN
The optimization of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly that possess a labile stereocenter at C3 is described. Quaternization of the C3 position of compound 1 in order to prevent racemization gave compound 2, which was inactive in our capsid disassembly assay. A likely explanation for this finding was revealed by in silico analysis predicting a dramatic increase in energy of the bioactive conformation upon quaternization of the C3 position. Replacement of the C3 of the diazepine ring with a nitrogen atom to give the 1,5-dihydro-benzo[f][1,3,5]triazepine-2,4-dione analog 4 was well tolerated. Introduction of a rigid spirocyclic system at the C3 position gave configurationally stable 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione analog 5, which was able to access the bioactive conformation without a severe energetic penalty and inhibit capsid assembly. Preliminary structure-activity relationships (SAR) and X-ray crystallographic data show that knowledge from the 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly can be transferred to these new scaffolds.
Asunto(s)
Fármacos Anti-VIH/química , Benzodiazepinas/química , Proteínas de la Cápside/antagonistas & inhibidores , VIH-1/metabolismo , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Benzodiazepinas/síntesis química , Benzodiazepinas/farmacología , Sitios de Unión , Proteínas de la Cápside/metabolismo , Cristalografía por Rayos X , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Estructura Terciaria de Proteína , Estereoisomerismo , Relación Estructura-Actividad , Ensamble de Virus/efectos de los fármacosRESUMEN
Detailed structure-activity relationships of the C3-phenyl moiety that allow for the optimization of antiviral potency of a series of 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione inhibitors of HIV capsid (CA) assembly are described. Combination of favorable substitutions gave additive SAR and allowed for the identification of the most potent compound in the series, analog 27. Productive SAR also transferred to the benzotriazepine and spirobenzodiazepine scaffolds, providing a solution to the labile stereocenter at the C3 position. The molecular basis of how compound 27 inhibits mature CA assembly is rationalized using high-resolution structural information. Our understanding of how compound 27 may inhibit immature Gag assembly is also discussed.
Asunto(s)
Fármacos Anti-VIH/química , Benzodiazepinas/química , Benzodiazepinonas/química , Proteínas de la Cápside/antagonistas & inhibidores , VIH-1/metabolismo , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Benzodiazepinas/síntesis química , Benzodiazepinas/farmacología , Benzodiazepinonas/síntesis química , Benzodiazepinonas/farmacología , Sitios de Unión , Células CACO-2 , Proteínas de la Cápside/metabolismo , Permeabilidad de la Membrana Celular/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Estructura Terciaria de Proteína , Estereoisomerismo , Relación Estructura-Actividad , Ensamble de Virus/efectos de los fármacosRESUMEN
The discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly is described. Synthesis of analogs of the 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hit established structure-activity relationships. Replacement of the enamine functionality of the hit series with either an imidazole or a pyrazole ring led to compounds that inhibited both capsid assembly and reverse transcriptase. Optimization of the bicyclic benzodiazepine scaffold to include a 3-phenyl substituent led to lead compound 48, a pure capsid assembly inhibitor with improved antiviral activity.
Asunto(s)
Fármacos Anti-VIH/química , Benzodiazepinonas/química , Proteínas de la Cápside/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Benzodiazepinonas/síntesis química , Benzodiazepinonas/farmacología , Proteínas de la Cápside/metabolismo , Evaluación Preclínica de Medicamentos , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismo , Humanos , Imidazoles/química , Pirazoles/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
The role of the tetrazole moiety in the binding of aryl thiotetrazolylacetanilides with HIV-1 wild type and K103N/Y181C double mutant reverse transcriptases was explored. Different acyclic, cyclic and heterocyclic replacements were investigated in order to evaluate the conformational and electronic contribution of the tetrazole ring to the binding of the inhibitors in the NNRTI pocket. The replacement of the tetrazole by a pyrazolyl group led to reversal of selectivity, providing inhibitors with excellent potency against the double mutant reverse transcriptase.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH/genética , Tetrazoles/síntesis química , Tetrazoles/farmacología , Fármacos Anti-VIH/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , VIH-1/efectos de los fármacos , VIH-1/genética , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tetrazoles/químicaRESUMEN
A series of aryl thiotetrazolylacetanilides were synthesized and found to be potent inhibitors of the HIV-1 wild type and K103N/Y181C double mutant reverse transcriptases. The incorporation of an alkynyl fragment on the aniline provided inhibitors with excellent cellular activity and extensive SAR led to the identification of one inhibitor having good oral bioavailability in rats.
Asunto(s)
Acetanilidas/farmacología , Antivirales/química , Antivirales/farmacología , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , VIH-1/genética , Acetanilidas/química , Animales , Disponibilidad Biológica , Modelos Moleculares , Estructura Molecular , Mutación , Ratas , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
High-throughput screening hit 1 was identified as a potent, broad-spectrum, non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 replication. Analysis of the bound conformation of analogs of this inhibitor via molecular modeling and NMR contributed to the design of novel tertiary amide, carbamate, and thiocarbamate based NNRTIs.
Asunto(s)
Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Inhibidores de la Transcriptasa Inversa/farmacología , Replicación Viral/efectos de los fármacos , Amidas/química , Fármacos Anti-VIH/síntesis química , Carbamatos/química , Diseño de Fármacos , Farmacorresistencia Viral , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Modelos Químicos , Inhibidores de la Transcriptasa Inversa/síntesis química , Relación Estructura-Actividad , Tiocarbamatos/químicaRESUMEN
Respiratory syncytial virus (RSV) is a major cause of respiratory illness in infants, immunocompromised patients, and the elderly. New antiviral agents would be important tools in the treatment of acute RSV disease. RSV encodes its own RNA-dependent RNA polymerase that is responsible for the synthesis of both genomic RNA and subgenomic mRNAs. The viral polymerase also cotranscriptionally caps and polyadenylates the RSV mRNAs at their 5' and 3' ends, respectively. We have previously reported the discovery of the first nonnucleoside transcriptase inhibitor of RSV polymerase through high-throughput screening. Here we report the design of inhibitors that have improved potency both in vitro and in antiviral assays and that also exhibit activity in a mouse model of RSV infection. We have isolated virus with reduced susceptibility to this class of inhibitors. The mutations conferring resistance mapped to a novel motif within the RSV L gene, which encodes the catalytic subunit of RSV polymerase. This motif is distinct from the catalytic region of the L protein and bears some similarity to the nucleotide binding domain within nucleoside diphosphate kinases. These findings lead to the hypothesis that this class of inhibitors may block synthesis of RSV mRNAs by inhibiting guanylylation of viral transcripts. We show that short transcripts produced in the presence of inhibitor in vitro do not contain a 5' cap but, instead, are triphosphorylated, confirming this hypothesis. These inhibitors constitute useful tools for elucidating the molecular mechanism of RSV capping and represent valid leads for the development of novel anti-RSV therapeutics.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , ARN Mensajero/metabolismo , ARN Polimerasa Dependiente del ARN/metabolismo , Virus Sincitiales Respiratorios/efectos de los fármacos , Virus Sincitiales Respiratorios/enzimología , Ribonucleoproteínas/farmacología , Administración Intranasal , Secuencia de Aminoácidos , Animales , Dominio Catalítico/genética , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Caperuzas de ARN/biosíntesis , Caperuzas de ARN/efectos de los fármacos , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/genética , Infecciones por Virus Sincitial Respiratorio/prevención & control , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitiales Respiratorios/fisiología , Ribonucleoproteínas/administración & dosificación , Ribonucleoproteínas/química , Alineación de Secuencia , Replicación Viral/efectos de los fármacosRESUMEN
A series of novel 8-substituted dipyridodiazepinone-based inhibitors were investigated for their antiviral activity against wild type human immunodeficiency virus (HIV-1) and the clinically prevalent K103N/Y181C mutant virus. Our efforts have resulted in a series of benzoic acid analogues that are potent inhibitors of HIV-1 replication against a panel of HIV-1 strains resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Furthermore, the combination of good antiviral potency, a broad spectrum of activity, and an excellent pharmacokinetic profile provides strong justification for the further development of compound (7) as a potential treatment for wild type and NNRTI-resistant HIV-1 infection.