RESUMO
Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.
Assuntos
Lisina-tRNA Ligase , Mycobacterium tuberculosis , Tuberculose , Animais , Lisina-tRNA Ligase/química , Lisina-tRNA Ligase/genética , Lisina-tRNA Ligase/farmacologia , Camundongos , Mycobacterium tuberculosis/genética , Tuberculose/tratamento farmacológicoRESUMO
The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB(1) antagonist with high predicted human oral bioavailability.
Assuntos
Indóis/farmacocinética , Receptor CB1 de Canabinoide/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Humanos , Indóis/administração & dosagem , Indóis/química , Relação Estrutura-AtividadeRESUMO
The previously described lead compound 5 is a potent and selective V(1A) antagonist with affinity at both the rat and human receptor, but displays poor oral bioavailability and moderate clearance. We report herein the successful optimisation of the pharmacokinetic (PK) properties to afford the potent, selective, orally bioavailable and CNS penetrant compound 15f. A custom optimisation approach was required which demonstrated the value of using early, rapid in vivo PK studies to show improvements in oral exposure. Such assays may be of particular value where low oral bioavailability is anticipated to be multifactorial (e.g., permeability, gut wall metabolism and/or transport) where satisfactory modelling of in vitro data is likely to be difficult within a drug discovery context.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Fenilalanina/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Masculino , Peptídeos/química , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacocinética , Ligação Proteica , Ratos , Ratos Wistar , Receptores de Vasopressinas/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The discovery and structure-activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB(1) antagonist.
Assuntos
Amidas/química , Indóis/química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacocinética , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Indóis/síntese química , Indóis/farmacocinética , Masculino , Camundongos , Modelos Moleculares , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
The discovery of a novel series of 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamide antagonists of the vasopressin V(1A) receptor is disclosed. Compounds 47 and 48 were found to be high affinity, selective vasopressin V(1A) antagonists.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Antagonistas dos Receptores de Hormônios Antidiuréticos , Descoberta de Drogas , Amidas/química , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Células Cultivadas , Ciclização , Humanos , Fígado/metabolismo , Estrutura Molecular , Ligação Proteica/efeitos dos fármacosRESUMO
Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.
Assuntos
Antituberculosos/química , Pirimidinonas/química , Animais , Antituberculosos/metabolismo , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Meia-Vida , Humanos , Ferro/metabolismo , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Microssomos/metabolismo , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Pirazóis/química , Pirimidinonas/metabolismo , Pirimidinonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This noncytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning from Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition, and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH-IMP-inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi-pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time-kill experiments in vitro suggest that sustained exposure to drug concentrations above the minimum inhibitory concentration (MIC) for 24 h were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis-infected animals and patients revealed 0.5-2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate-dependent effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB.
Assuntos
Antituberculosos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Sulfonamidas/farmacologia , Animais , Desenho de Fármacos , Descoberta de Drogas , Farmacorresistência Bacteriana , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Mutação , Conformação Proteica , Coelhos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Tuberculose/tratamento farmacológicoRESUMO
A series of secondary face modified cyclodextrins (CDs) were synthesised with the aim of constructing host molecules capable of forming host-guest complexes with neuromuscular blockers, especially with rocuronium bromide. Perfacial 2-O-substitution of gamma-CD with 4-carboxybenzyl resulted in a CD host molecule 1 that forms a 1:1 binary complex with rocuronium bromide (K(a) 6.2 x 10(5) M(-1)). The biological activities of this compound and other derivatives as reversal agents of rocuronium bromide were examined in vitro (mouse hemi-diaphragm) and in vivo (anaesthetized guinea pigs). The host molecule 1 was found to exert potent reversal activity (ED(50) 0.21 micromol/kg, iv) against rocuronium-induced neuromuscular block, and thus proved the viability of using host molecules as antidotes of a biologically active compound.
Assuntos
Androstanóis/antagonistas & inibidores , Ciclodextrinas/síntese química , Ciclodextrinas/farmacologia , Fármacos Neuromusculares não Despolarizantes/antagonistas & inibidores , Androstanóis/farmacologia , Animais , Ciclodextrinas/química , Diafragma/efeitos dos fármacos , Diafragma/fisiologia , Cobaias , Técnicas In Vitro , Masculino , Camundongos , Estrutura Molecular , Relaxamento Muscular/efeitos dos fármacos , Bloqueio Neuromuscular , Fármacos Neuromusculares não Despolarizantes/farmacologia , Rocurônio , Relação Estrutura-AtividadeRESUMO
A novel series of alpha-amino-acid phenolic ester derivatives containing sulphide, sulphoxide, sulphone, ester and amide side chains were prepared and shown to display potent intravenous anaesthetic activity.
Assuntos
Aminoácidos/síntese química , Aminoácidos/farmacologia , Anestésicos Intravenosos/síntese química , Anestésicos Intravenosos/farmacologia , Fenóis/síntese química , Fenóis/farmacologia , Animais , Ésteres , Antagonistas de Receptores de GABA-A , Masculino , Camundongos , Equilíbrio Postural/efeitos dos fármacos , Propofol/farmacologia , Reflexo/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A number of water soluble bis-amino-2,6-dimethoxyphenyl ester derivatives were found to exhibit improved anaesthetic activity in mice relative to propofol 1. Of the analogues disclosed, 44 was further profiled in rodents and found to be a superior agent to propofol for the induction and maintenance of anaesthesia.