RESUMO
Synthetic neamine mimetics have been evaluated for binding to the HIV-1 Rev response element. Modified neamine derivatives, obtained from reductive amination of neamine, led to identification of new 6-amino modified neamine-type ligands with HIV-1 RRE binding affinity up to 20× that of neamine and up to 6× that of the more complex neomycin itself. This provides a noteworthy structure-activity increase and a useful lead to simplified, chemically accessible mimetics.
Assuntos
Fármacos Anti-HIV/farmacologia , Framicetina/farmacologia , HIV-1/efeitos dos fármacos , Neomicina/farmacologia , RNA Viral/efeitos dos fármacos , Elementos de Resposta/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Framicetina/síntese química , Framicetina/química , Estrutura Molecular , Neomicina/análogos & derivados , Neomicina/química , Relação Estrutura-AtividadeRESUMO
There is an important medical need for new antifungal agents with novel mechanisms of action to treat the increasing number of patients with life-threatening systemic fungal disease and to overcome the growing problem of resistance to current therapies. F901318, the leading representative of a novel class of drug, the orotomides, is an antifungal drug in clinical development that demonstrates excellent potency against a broad range of dimorphic and filamentous fungi. In vitro susceptibility testing of F901318 against more than 100 strains from the four main pathogenic Aspergillus spp. revealed minimal inhibitory concentrations of ≤0.06 µg/mL-greater potency than the leading antifungal classes. An investigation into the mechanism of action of F901318 found that it acts via inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) in a fungal-specific manner. Homology modeling of Aspergillus fumigatus DHODH has identified a predicted binding mode of the inhibitor and important interacting amino acid residues. In a murine pulmonary model of aspergillosis, F901318 displays in vivo efficacy against a strain of A. fumigatus sensitive to the azole class of antifungals and a strain displaying an azole-resistant phenotype. F901318 is currently in late Phase 1 clinical trials, offering hope that the antifungal armamentarium can be expanded to include a class of agent with a mechanism of action distinct from currently marketed antifungals.
RESUMO
Target-focused compound libraries are collections of compounds which are designed to interact with an individual protein target or, frequently, a family of related targets (such as kinases, voltage-gated ion channels, serine/cysteine proteases). They are used for screening against therapeutic targets in order to find hit compounds that might be further developed into drugs. The design of such libraries generally utilizes structural information about the target or family of interest. In the absence of such structural information, a chemogenomic model that incorporates sequence and mutagenesis data to predict the properties of the binding site can be employed. A third option, usually pursued when no structural data are available, utilizes knowledge of the ligands of the target from which focused libraries can be developed via scaffold hopping. Consequently, the methods used for the design of target-focused libraries vary according to the quantity and quality of structural or ligand data that is available for each target family. This article describes examples of each of these design approaches and illustrates them with case studies, which highlight some of the issues and successes observed when screening target-focused libraries.
Assuntos
Desenho de Fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Humanos , Canais Iônicos/metabolismo , Modelos Moleculares , Ligação Proteica , Mapeamento de Interação de Proteínas , Proteínas Quinases/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMO
A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.
Assuntos
Compostos de Boro/química , Ácidos Borônicos/química , Compostos Macrocíclicos/química , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Sítios de Ligação , Compostos de Boro/síntese química , Compostos de Boro/farmacologia , Domínio Catalítico , Cristalografia por Raios X , Hepacivirus/efeitos dos fármacos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
We have designed and synthesized a novel series of alpha-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described.
Assuntos
Ácidos Borônicos/síntese química , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Ácidos Borônicos/farmacologia , Ácidos Borônicos/uso terapêutico , Domínio Catalítico , Desenho de Fármacos , Hepacivirus/enzimologia , Estrutura Molecular , Serina/química , Relação Estrutura-AtividadeRESUMO
A practical asymmetric synthesis of a highly substituted N-acylpyrrolidine on multi-kilogram scale is described. The key step in the construction of the three stereocenters is a [3+2] cycloaddition of methyl acrylate and an imino ester prepared from l-leucine t-butyl ester hydrochloride and 2-thiazolecarboxaldehyde. The cycloaddition features novel asymmetric catalysis via a complex of silver acetate and a cinchona alkaloid, particularly hydroquinine, with complete diastereomeric control and up to 87% enantiomeric control. The alkaloid serves as a ligand as well as a base for the formation of the azomethine ylide or 1,3-dipole. Experiments have shown that the hydroxyl group of hydroquinine is a critical element for the enantioselectivities observed. The cycloaddition methodology is also applicable to methylvinyl ketone, providing access to either alpha- or beta-epimers of 4-acetylpyrrolidine depending on the reaction conditions utilized. The synthesis also highlights an efficient N-acylation, selective O- versus N-methylation, and a unique ester reduction with NaBH4-MeOH catalyzed by NaB(OAc)3H that not only achieves excellent chemoselectivity but also avoids formation of the undesired but thermodynamically favored epimer. The highly functionalized target is synthesized in seven linear steps from l-leucine t-butyl ester hydrochloride with all three isolated intermediates being highly crystalline.
Assuntos
RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Hepacivirus/enzimologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Acrilatos/química , Acilação , Alcaloides/química , Cristalografia por Raios X , RNA Polimerases Dirigidas por DNA/metabolismo , Iminas/química , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/química , Prata/química , Solventes , EstereoisomerismoRESUMO
The SAR development is described for a series of N-acyl pyrrolidine inhibitors of the Hepatitis C virus RNA-dependent RNA polymerase, NS5B, from tractable Delta21 enzyme inhibitors to an example with antiviral activity in a cellular assay (HCV replicon).
Assuntos
Antivirais/farmacologia , Química Farmacêutica/métodos , Hepacivirus/química , Hepacivirus/genética , Pirrolidinas/antagonistas & inibidores , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Replicon/genética , Proteínas não Estruturais Virais/farmacologia , Antivirais/química , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , RNA Viral/química , Proteínas não Estruturais Virais/química , Replicação Viral/efeitos dos fármacosRESUMO
Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Pirrolidinas/síntese química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacologia , Sítios de Ligação , Disponibilidade Biológica , Chlorocebus aethiops , Hepacivirus/enzimologia , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacologia , RNA Polimerase Dependente de RNA/química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Células VeroRESUMO
[reaction: see text] In this, the first of two Letters, we describe how a P3/P4 urea linking unit was used to greatly enhance the biochemical and replicon potency of inhibitors based upon the pyrrolidine-5,5-trans-lactam template. Compound 7b demonstrated a 100 nM IC(50) in the replicon cell-based surrogate HCV assay.
Assuntos
Antivirais/síntese química , Hepacivirus/enzimologia , Lactamas/química , Inibidores de Proteases/síntese química , Pirrolidinas/química , Ureia/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacologia , Cristalografia por Raios X , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Concentração Inibidora 50 , Conformação Molecular , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
[reaction: see text] In this, the second of two Letters, the optimization of the pyrrolidine-5,5-trans-lactam template (exemplified by 1a) as a mechanism-based inhibitor of hepatitis C NS3/4A protease is described. "Right Box" analysis of cassette dosing screening pharmacokinetic data was used to rapidly categorize the compounds. GW0014 (compound 4d) emerged as the compound displaying an optimal balance of biochemical and replicon potency, along with low i.v. clearance in the dog.
Assuntos
Lactamas/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Pirrolidinas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Concentração Inibidora 50 , Estrutura Molecular , Inibidores de Proteases/química , Proteínas não Estruturais Virais/metabolismoRESUMO
We report methodology which enables direct phosphorylation of 3'-deoxycytidine exclusively either at the 5'-hydroxyl or the 2'-hydroxyl. Protection of the base is not required. Standard phosphoramidochloridates in combination with pyridine and tert-butyl magnesium chloride is employed, in which the ratio of nucleoside to Grignard reagent is crucial. These findings, which appear to be general for 3'-deoxycytidines, are not applicable to 3'-deoxyuridine or 3'-deoxyguanosine.
Assuntos
Desoxicitidina/análogos & derivados , Desoxicitidina/síntese química , Hidroxilação , Indicadores e Reagentes , Fosforilação , EstereoisomerismoRESUMO
The pyrrolidine-5,5-trans-lactam template was used to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease displaying potent activity in the replicon cell-based assay. The activity of this series is not dependent upon its chemical reactivity and molecules have been synthesised which combine enhanced biochemical potency with improved plasma stability. Promising initial pharmacokinetic data indicating the potential for further optimisation of this series into low molecular weight, drug-like inhibitors is presented.
Assuntos
Desenho de Fármacos , Hepacivirus/enzimologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Cristalografia por Raios X , Cães , Estabilidade de Medicamentos , Hepacivirus/efeitos dos fármacos , Humanos , Injeções Intravenosas , Lactamas/síntese química , Lactamas/farmacocinética , Lactamas/farmacologia , Modelos Biológicos , Estrutura Molecular , Inibidores de Proteases/farmacocinética , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ratos , Proteínas não Estruturais Virais/metabolismoRESUMO
Using the pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 2b, with a spiro-cyclobutyl P1 substituent and an isopropyl carbonyl substituent at the lactam nitrogen, has an IC(50) value in the replicon cell-based assay of 3 microM.
Assuntos
Lactamas/farmacologia , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Desenho de Fármacos , Estabilidade de Medicamentos , Concentração Inibidora 50 , Lactamas/síntese química , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
[reaction: see text] In this, the first of two letters, we outline the use of the pyrrolidine-5,5-trans-lactam template to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. The hitherto unreported reaction of the acyl iminium ion precursor 4 with dialkyl-substituted silyl ketene acetals (e.g., 8b) is described. Compound 12b, with a spirocyclobutyl P1 substituent and a cyclopropylacyl substituent on the lactam nitrogen, has a k(obs)/I of 400 M(-)(1) s(-)(1) and demonstrates activity in a replicon cell-based surrogate HCV assay.
Assuntos
Hepacivirus/enzimologia , Lactamas/síntese química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Pirrolidinas/síntese química , Serina Endopeptidases/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Linhagem Celular , Desenho de Fármacos , Estabilidade de Medicamentos , Hepacivirus/efeitos dos fármacos , Humanos , Lactamas/química , Estrutura Molecular , Inibidores de Proteases/química , Pirrolidinas/química , Proteínas não Estruturais Virais/metabolismoRESUMO
[reaction: see text] In this, the second of two letters, we describe the elaboration of the pyrrolidine-5,5-trans-lactam template to delineate the requirements for optimal substitution of the pyrrolidine and lactam nitrogen atoms. Central to the strategy is the use of rapid iterative synthesis in conjunction with X-ray crystal structure determination of ligand-protein complexes.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Lactamas/síntese química , Pirrolidinas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Linhagem Celular , Cristalografia por Raios X , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Concentração Inibidora 50 , Lactamas/química , Lactamas/farmacologia , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Pirrolidinas/química , Pirrolidinas/farmacologia , Proteínas não Estruturais Virais/metabolismoRESUMO
Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM.