RESUMO
Spider venom toxins, such as Protoxin-II (ProTx-II), have recently received much attention as selective Nav1.7 channel blockers, with potential to be developed as leads for the treatment of chronic nocioceptive pain. ProTx-II is a 30-amino acid peptide with three disulfide bonds that has been reported to adopt a well-defined inhibitory cystine knot (ICK) scaffold structure. Potential drawbacks with such peptides include poor pharmacodynamics and potential scrambling of the disulfide bonds in vivo. In order to address these issues, in the present study we report the solid-phase synthesis of lanthionine-bridged analogues of ProTx-II, in which one of the three disulfide bridges is replaced with a thioether linkage, and evaluate the biological properties of these analogues. We have also investigated the folding and disulfide bridging patterns arising from different methods of oxidation of the linear peptide precursor. Finally, we report the X-ray crystal structure of ProTx-II to atomic resolution; to our knowledge this is the first crystal structure of an ICK spider venom peptide not bound to a substrate.
Assuntos
Dissulfetos/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Peptídeos/farmacologia , Venenos de Aranha/farmacologia , Aranhas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Cristalografia por Raios X , Dissulfetos/química , Modelos Moleculares , Conformação Molecular/efeitos dos fármacos , Peptídeos/química , Venenos de Aranha/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/químicaRESUMO
A pharmacophore model was built, based on known CGRP receptor antagonists, and this was used to aid the identification of novel leads. Analogues were designed, modelled and synthesised which incorporated alternative 'LHS' fragments linked via either an amide or urea to a privileged 'RHS' fragment commonly found in CGRP receptor antagonists. As a result a novel series of oxadiazole CGRP receptor antagonists has been identified and the subsequent optimisation to enhance both potency and bioavailability is presented.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Desenho de Fármacos , Transtornos de Enxaqueca/tratamento farmacológico , Oxidiazóis/síntese química , Oxidiazóis/uso terapêutico , Administração Oral , Animais , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/química , RatosRESUMO
We describe the discovery of a series of pyrazole amide EP(1) receptor antagonists with good aqueous solubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic group in the region of the molecule previously occupied by a carboxylic acid, which was known to be a key element of the pharmacophore. This study led to the identification of compounds such as 4h, 4j and 10b which demonstrated brain-to-blood ratios of 0.8:1-2.0:1 in addition to good solubility and metabolic stability.
Assuntos
Encéfalo/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Pirazóis/química , Receptores de Prostaglandina E/antagonistas & inibidores , Amidas/química , Ácidos Carboxílicos/química , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Isoquinolinas/química , Modelos Químicos , Estrutura Molecular , Receptores de Prostaglandina E Subtipo EP1 , Solubilidade , Relação Estrutura-AtividadeRESUMO
Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP(1) receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain.
Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Analgésicos/química , Animais , Encéfalo/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Técnicas de Química Combinatória , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estrutura Molecular , Medição da Dor , Pirazóis/química , Ratos , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-AtividadeRESUMO
We describe the SAR, in terms of heterocyclic replacements, for a series of pyrazole EP(1) receptor antagonists. This study led to the identification of several aromatic heterocyclic replacements for the pyrazole in the original compound. Investigation of replacements for the methylene linker uncovered disparate SAR in the thiazole and pyridine series.
Assuntos
Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-AtividadeRESUMO
We describe the generation of novel EP(1) receptor antagonists by investigation of thiophene isosteres. In addition, we disclose preliminary in vitro and in vivo DMPK for selected compounds.
Assuntos
Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Técnicas In Vitro , Ratos , Receptores de Prostaglandina E Subtipo EP1RESUMO
Novel, low molecular weight inhibitors of IMPDH have been discovered through the application of a validated virtual screening protocol. A series of 21 IMPDH inhibitors were used to validate the docking procedure. Application of this procedure to the selection of compounds for screening from an in-house database resulted in a 50-fold reduction in the size of the screening set (3425 to 74 compounds) and gave a hit-rate of 10% on biological evaluation.
Assuntos
Simulação por Computador , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/química , IMP Desidrogenase/antagonistas & inibidores , Sítios de Ligação , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Modelos Moleculares , Peso Molecular , Relação Estrutura-Atividade , ÁguaRESUMO
Starting from the tetrapeptide Ac-pYEEI-NHMe and using a structure-based approach, we have designed and synthesised a peptidomimetic ligand for p56(lck) SH2 domain containing a conformationally restricted replacement for the two glutamate residues. We have explored replacments for the isoleucine residue in the pY+3 pocket and thus identified 1-(R)-amino-3-(S)-indaneacetic acid as the most potent replacement. We also report the X-ray crystal structures of two of the antagonists.