RESUMO
A series of heterocyclic aza-analogs of BI 207524 (2), a potent HCV NS5B polymerase thumb pocket 1 inhibitor, was investigated with the goal to reduce the liability associated with the release of a genotoxic aniline metabolite in vivo. Analog 4, containing a 2-aminopyridine aniline isostere that is negative in the Ames test was identified, and was found to provide comparable GT1a/1b potency to 2. Although the cross-species PK profile, poor predicted human liver distribution of analog 4 and allometry principles projected high doses to achieve a strong antiviral response in patients, this work has provided a path forward toward the design of novel thumb pocket 1 NS5B polymerase inhibitors with improved safety profiles.
Assuntos
Acrilatos/metabolismo , Acrilatos/farmacologia , Compostos de Anilina/metabolismo , Antivirais/metabolismo , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Indóis/metabolismo , Indóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Acrilatos/química , Acrilatos/farmacocinética , Animais , Antivirais/química , Antivirais/farmacocinética , Cães , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Haplorrinos , Hepacivirus/enzimologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Indóis/química , Indóis/farmacocinética , Ratos , Proteínas não Estruturais Virais/metabolismoRESUMO
A prodrug approach was developed to address the low oral bioavailability of a poorly soluble (<0.1µg/mL in pH 6.8 buffer) but highly permeable thumb pocket 1 HCV NS5B polymerase inhibitor. Bioconversion rates of structurally diverse prodrug derivatives were evaluated in a panel of in vitro assays using microsomes, from either liver or intestinal tissues, simulated intestinal fluids, simulated gastric fluids or plasma. In vivo bioconversion of promising candidates was evaluated following oral administration to rats. The most successful strategy involved modification of the parent drug carboxylic acid moiety to glycolic amide esters which improved solubility in lipid-based self-emulsifying drug delivery systems (SEDDS). Crystalline prodrug analog 36 (mp 161°C) showed good solubility in individual SEDDS components (up to 80mg/mL) compared to parent 2 (<3mg/mL; mp 267°C) and cross-species bioconversions which correlated with in vitro stability in liver microsomes.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Inibidores da Síntese de Ácido Nucleico/administração & dosagem , Pró-Fármacos/administração & dosagem , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Emulsões/química , Emulsões/metabolismo , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Inibidores da Síntese de Ácido Nucleico/química , Inibidores da Síntese de Ácido Nucleico/metabolismo , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Ratos , Solubilidade , Proteínas não Estruturais Virais/metabolismoRESUMO
We describe our efforts to identify analogs of thumb pocket 1 HCV NS5B inhibitor 1 (aza-analog of BI 207524) with improved plasma to liver partitioning and a predicted human half-life consistent with achieving a strong antiviral effect at a reasonable dose in HCV-infected patients. Compounds 3 and 7 were identified that met these criteria but exhibited off-target promiscuity in an in vitro pharmacology screen and in vivo toxicity in rats. High lipophilicity in this class was found to correlate with increased probability for promiscuous behavior and toxicity. The synthesis of an 8×11 matrix of analogs allowed the identification of C3, an inhibitor that displayed comparable potency to 1, improved partitioning to the liver and reduced lipophilicity. Although C3 displayed reduced propensity for in vitro off-target inhibition and the toxicity profile in rats was improved, the predicted human half-life of this compound was short, resulting in unacceptable dosing requirements to maintain a strong antiviral effect in patients.
Assuntos
Acrilatos/química , Acrilatos/farmacologia , Antivirais/química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Acrilatos/farmacocinética , Acrilatos/toxicidade , Animais , Antivirais/farmacocinética , Antivirais/toxicidade , Cães , Haplorrinos , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Indóis/farmacocinética , Indóis/toxicidade , Lipídeos/química , Fígado/metabolismo , Fígado/virologia , Ratos , Proteínas não Estruturais Virais/metabolismoRESUMO
Optimization efforts on the anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors 1 and 2 resulted in the identification of multiple structural elements that contributed to improved cell culture potency. The additive effect of these elements resulted in compound 46, an inhibitor with enzymatic (IC50) and cell culture (EC50) potencies of less than 100 nanomolar.
Assuntos
Antivirais/química , Inibidores Enzimáticos/química , Hepacivirus/enzimologia , Proteínas não Estruturais Virais/antagonistas & inibidores , ortoaminobenzoatos/química , Antivirais/síntese química , Antivirais/farmacologia , Sítios de Ligação , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/farmacologiaRESUMO
A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis. Structure-based drug design strategies led to the discovery of potent sub-micromolar inhibitors 11a-c and 12a-c from a weak-binding fragment-like structure 1 as a starting point.
Assuntos
Antivirais/química , Inibidores Enzimáticos/química , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/farmacologia , Sítios de Ligação , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Hepacivirus/enzimologia , Humanos , Simulação de Acoplamento Molecular , Nucleosídeos/química , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , ortoaminobenzoatos/químicaRESUMO
We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50<200nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B-ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors.
Assuntos
Antivirais/química , Desenho de Fármacos , Hepacivirus/enzimologia , Quinazolinonas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Hepacivirus/fisiologia , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos , ortoaminobenzoatos/químicaRESUMO
Replacement of the benzimidazole core of allosteric Thumb Pocket 1 HCV NS5B finger loop inhibitors by more lipophilic indole derivatives provided up to 30-fold potency improvements in cell-based subgenomic replicon assays. Optimization of C-2 substitution on the indole core led to the identification of analogs with EC(50)<100 nM and modulated the pharmacokinetic properties of the inhibitors based on preliminary data from in vitro ADME profiles and in vivo rat PK.
Assuntos
Amidas/química , Benzimidazóis/síntese química , Hepacivirus/efeitos dos fármacos , Indóis/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Amidas/síntese química , Amidas/farmacologia , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Células CACO-2 , Hepacivirus/enzimologia , Hepacivirus/genética , Humanos , Indóis/química , Indóis/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Ratos , Solubilidade , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/genéticaRESUMO
In this part 2, new indole 5-carboxamide Thumb Pocket 1 inhibitors of HCV NS5B polymerase are described. Structure-activity relationships (SAR) were explored at the central amino acid linker position and the right-hand-side of the molecule in an attempt to identify molecules with a balanced overall profile of potency (EC(50)<100 nM), physicochemical properties and ADME characteristics.
Assuntos
Aminoácidos/química , Benzimidazóis/síntese química , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Indóis/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Sequência de Aminoácidos , Aminoácidos/síntese química , Aminoácidos/farmacologia , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Células CACO-2 , Hepacivirus/genética , Humanos , Indóis/química , Indóis/farmacologia , Concentração Inibidora 50 , Dados de Sequência Molecular , Estrutura Molecular , Ratos , Solubilidade , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/genéticaRESUMO
Significant advances have led to receptor induced-fit and conformational selection models for describing bimolecular recognition, but a more comprehensive view must evolve to also include ligand shape and conformational changes. Here, we describe an example where a ligand's "structural hinge" influences potency by inducing an "L-shape" bioactive conformation, and due to its solvent exposure in the complex, reasonable conformation-activity-relationships can be qualitatively attributed. From a ligand design perspective, this feature was exploited by successful linker hopping to an alternate "structural hinge" that led to a new and promising chemical series which matched the ligand bioactive conformation and the pocket bioactive space. Using a combination of X-ray crystallography, NMR and modeling with support from binding-site resistance mutant studies and photoaffinity labeling experiments, we were able to derive inhibitor-polymerase complexes for various chemical series.
Assuntos
Diamida/química , Diamida/farmacologia , Descoberta de Drogas , Hepacivirus , Indóis/química , Conformação Molecular , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Diamida/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Ligantes , Modelos Moleculares , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismoRESUMO
Previously described SAR of benzimidazole-based non-nucleoside finger loop (Thumb Pocket I) inhibitors of HCV NS5B polymerase was expanded. Prospecting studies using parallel synthesis techniques allowed the rapid identification of novel cinnamic acid right-hand sides that provide renewed opportunities for further optimization of these inhibitors. Novel diamide derivatives such as 44 exhibited comparable potency (enzymatic and cell-based HCV replicon) as previously described tryptophan-based inhibitors but physicochemical properties (e.g., aqueous solubility and lipophilicity) have been improved, resulting in molecules with reduced off-target liabilities (CYP inhibition) and increased metabolic stability.
Assuntos
Antivirais/síntese química , Benzimidazóis/química , Diamida/síntese química , Inibidores Enzimáticos/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Antivirais/química , Antivirais/farmacologia , Cinamatos/química , Diamida/química , Diamida/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Microssomos Hepáticos/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
SAR at the C-2 position of benzimidazole-based Thumb Pocket I inhibitors of HCV NS5B polymerase revealed parallel activity for distinct sub-series that harbor 5-hydroxytryptophan amides, neutral thiazole isosteres or recently disclosed cinnamic acid diamides. The consistent SAR among the three sub-series suggest a common binding mode to the Thumb Pocket I allosteric site. New inhibitors with sub-micromolar cell-based replicon potency and improved 'drug-like' features are disclosed along with preliminary characterization of their ADME-PK profile.
Assuntos
Benzimidazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Benzimidazóis/sangue , Benzimidazóis/química , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/química , Humanos , Ratos , Relação Estrutura-AtividadeRESUMO
SAR studies at the N(1)-position of allosteric indole-based HCV NS5B inhibitors has led to the discovery of acetamide derivatives with good cellular potency in subgenomic replicons (EC(50) <200 nM). This class of inhibitors displayed improved physicochemical properties and favorable ADME-PK profiles over previously described analogs in this class.
Assuntos
Acetamidas/química , Antivirais/síntese química , Ácidos Carboxílicos/química , Descoberta de Drogas , Hepacivirus/enzimologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Acetamidas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Antivirais/farmacologia , Células CACO-2 , Ácidos Carboxílicos/farmacologia , Linhagem Celular , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , RNA Polimerases Dirigidas por DNA/metabolismo , Descoberta de Drogas/métodos , Hepacivirus/efeitos dos fármacos , Humanos , Microssomos Hepáticos/enzimologia , RNA Polimerase Dependente de RNA/metabolismo , Proteínas não Estruturais Virais/metabolismoRESUMO
The severe health conditions associated with chronic HCV infection remain a global concern. Small-molecule drugs that specifically target essential virally encoded enzymes have not yet progressed to market, and the current standard of care continues to rely on a combination of pegylated IFN with ribavirin. This therapy has serious side effects and a significant proportion of patients infected with HCV genotype 1 (the major genotype in industrialized countries) have an unsatisfactory outcome with this therapy. Major advances have been realized in the development of specific non-nucleoside inhibitors of the viral NS5B RNA-dependent RNA polymerase. This well-characterized replicative enzyme is a highly drugable target that, in addition to its active site, features at least three known allosteric binding pockets that regulate RNA synthesis and are suitable for inhibitor design. Clinical proof-of-concept for allosteric non-nucleoside HCV polymerase inhibitors has been reported and several compounds have progressed into preclinical studies. It is likely that in the future NS5B inhibitors will form an integral part of more effective anti-HCV therapies, combining the use of small-molecule antiviral drugs with or without the assistance of immune modulators such as IFNs in order to minimize the emergence of resistance.
Assuntos
Antivirais , Inibidores Enzimáticos , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Sítio Alostérico , Antivirais/farmacologia , Antivirais/uso terapêutico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Hepacivirus/química , Hepacivirus/enzimologia , Humanos , Conformação Proteica , RNA Polimerase Dependente de RNA/química , RNA Polimerase Dependente de RNA/metabolismo , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
The hepatitis C virus (HCV) infects millions of people wzorldwzide and currently available therapies suffer from limited efficacy and severe side effects. This review describes the discovery of a novel class of non-nucleoside HCV non-structural protein 5B (NS5B) polymerase inhibitors that inhibit the replication of viral RNA by binding to an allosteric site on the enzyme. Initial lead compounds based on a benzimidazole scaffold were optimized yielding novel indole derivatives with sub-micromolar activity in a cell-based replicon assay. X-ray crystallographic studies suggest that inhibitor binding interferes with the conformational movements of the protein that are necessary for enzyme activity. Finger loop inhibitors of HCV NS5B show potential for the development of novel anti-HCV therapeutics.
Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , HumanosRESUMO
Millions of people worldwide are infected with the hepatitis C virus (HCV), for which the main current therapy is associated with severe side effects, limited efficacy, is contraindicated in many patients, and has issues of compliance. As a result, new HCV therapies that are more effective and better tolerated are required. This review describes the discovery of a new class of allosteric, non-nucleoside HCV polymerase inhibitors that demonstrate potential for the development of novel anti-HCV therapeutics.
Assuntos
Hepacivirus/enzimologia , Hepatite C/tratamento farmacológico , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Benzimidazóis/uso terapêutico , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Humanos , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , RNA Polimerase Dependente de RNA/química , RNA Polimerase Dependente de RNA/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismoRESUMO
The interaction of the hepatitis C virus (HCV) RNA-dependent RNA polymerase with RNA substrate is incompletely defined. We have characterized the activities of the HCV NS5B polymerase, modified by different deletions and affinity tags, with a routinely used homopolymeric substrate, and established apparent affinities of the various NS5B constructs both for the NTP and the template/primer substrates. We identified a uniquely tagged HCV NS5B RNA polymerase construct with a lower affinity (higher K(m)) than mature HCV NS5B for template/ primer substrate and highlighted the use of such a polymerase for the identification of inhibitors of NS5B activity, particularly inhibitors of productive RNA binding. The characterization of specific benzimidazole-5-carboxamide-based inhibitors, identified in a screening campaign, revealed that this class of compounds was non-competitive with regard to NTP incorporation and had no effect on processive elongation, but inhibited an initiation phase of the HCV polymerase activity. The potency of these compounds versus a panel of different NS5B polymerase constructs was inversely proportional to the enzymes' affinities for template/primer substrate. The benzimidazole-5-carboxamide compounds also inhibited the full-length, untagged NS5B de novo initiation reaction using HCV 3'-UTR substrate RNA and expand the diversifying pool of potential HCV replication inhibitors.
Assuntos
Inibidores Enzimáticos/farmacologia , Hepacivirus/enzimologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/metabolismo , RNA/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Amidas/química , Amidas/farmacologia , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Bovinos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Hepacivirus/genética , Hepacivirus/fisiologia , Concentração Inibidora 50 , Cinética , Poliovirus/enzimologia , RNA/genética , RNA Polimerase II/metabolismo , RNA Viral/biossíntese , RNA Viral/genética , RNA Polimerase Dependente de RNA/genética , Especificidade por Substrato , Moldes Genéticos , Proteínas não Estruturais Virais/genética , Replicação Viral/efeitos dos fármacosRESUMO
A previously disclosed series of non-nucleoside allosteric inhibitors of the NS5B polymerase of the hepatitis C virus (HCV) was optimized to yield novel compounds with improved physicochemical properties and activity in cell-based assays. Replacement of ionizable carboxylic acids with neutral substituents in lead compounds produced inhibitors with cellular permeability and antiviral activity in a cell-based assay of subgenomic HCV RNA replication (replicon EC(50) as low as 1.7 microM). The improvement in potency in this ex vivo model of HCV RNA replication validates, in part, the mechanism by which this class of allosteric benzimidazole derivatives inhibits the polymerase and represents a significant step forward in the discovery of novel HCV therapeutics.
Assuntos
Antivirais/síntese química , Benzimidazóis/síntese química , Inibidores Enzimáticos/síntese química , Hepacivirus/efeitos dos fármacos , Replicon/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Antivirais/farmacologia , Benzimidazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/genética , Humanos , Relação Estrutura-AtividadeRESUMO
The spread of hepatitis C virus (HCV) infections and serious health consequences associated with chronic states of the disease have become a global concern. Small-molecule drugs that are specific for anti-HCV chemotherapy are not available and the current treatments for this disease suffer from limited success. The NS5B RNA-dependent RNA polymerase of HCV is an essential enzyme for viral replication. It has emerged in the last years as the most 'drugable' target of the entire HCV genome. While no agents from this class have yet demonstrated sustained efficacy in infected patients, early stage proof-of-concept has been achieved in the clinic, providing validation of the approach for antiviral therapy. This review provides a comprehensive account of the progress made towards the discovery of anti-HCV therapeutics based on inhibition of the virally encoded NS5B polymerase.
Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Hepatite C/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Sítios de Ligação/efeitos dos fármacos , Hepacivirus/química , Humanos , Nucleosídeos/farmacologia , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismoRESUMO
The synthesis of BILN 2061, an NS3 protease inhibitor with proven antiviral effect in humans, was accomplished in a convergent manner from four building blocks. The procedure described here was suitable for the preparation of multigram quantities of BILN 2061 for preclinical pharmacological evaluation.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Carbamatos/síntese química , Carbamatos/farmacologia , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Carbamatos/química , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Humanos , Compostos Macrocíclicos/química , Estrutura Molecular , Inibidores de Proteases/química , Quinolinas/química , Tiazóis/química , Proteínas não Estruturais Virais/metabolismoRESUMO
Enantiomerically pure N,N-dibenzyl-alpha-amino aldehydes reacted with (chloromethyl)lithium, generated in situ from bromochloromethane and lithium metal, to give predominantly erythro aminoalkyl epoxides. Treatment of the crude epoxides with aqueous hydrochloric acid gave crystalline (2S,3S)-N,N-dibenzylamino chlorohydrin hydrochlorides in 32-56% overall yield and high isomeric purity. These compounds are versatile synthetic intermediates for the preparation of hydroxyethylamine-based HIV protease inhibitors, either directly as such, or via conversion to the corresponding N-Boc-(2S,3S)-aminoalkyl epoxides. The processes described do not make use of hazardous reagents or intermediates, do not require chromatographic purifications, and are thus amenable to the preparation of large quantities of these versatile building blocks.