RESUMEN
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.
Asunto(s)
Lisina-ARNt Ligasa , Mycobacterium tuberculosis , Tuberculosis , Animales , Lisina-ARNt Ligasa/química , Lisina-ARNt Ligasa/genética , Lisina-ARNt Ligasa/farmacología , Ratones , Mycobacterium tuberculosis/genética , Tuberculosis/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Antituberculosos/química , Pirimidinonas/química , Animales , Antituberculosos/metabolismo , Antituberculosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Semivida , Humanos , Hierro/metabolismo , Masculino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana , Microsomas/metabolismo , Mutación , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/aislamiento & purificación , Pirazoles/química , Pirimidinonas/metabolismo , Pirimidinonas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antituberculosos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/enzimología , Sulfonamidas/farmacología , Animales , Diseño de Fármacos , Descubrimiento de Drogas , Farmacorresistencia Bacteriana , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Mutación , Conformación Proteica , Conejos , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinética , Tuberculosis/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Fenilalanina/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Humanos , Masculino , Péptidos/química , Fenilalanina/síntesis química , Fenilalanina/química , Fenilalanina/farmacocinética , Unión Proteica , Ratas , Ratas Wistar , Receptores de Vasopresinas/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas , Descubrimiento de Drogas , Amidas/química , Compuestos Aza/síntesis química , Compuestos Aza/química , Compuestos Aza/farmacología , Células Cultivadas , Ciclización , Humanos , Hígado/metabolismo , Estructura Molecular , Unión Proteica/efectos de los fármacosRESUMEN
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.
Asunto(s)
Indoles/farmacocinética , Receptor Cannabinoide CB1/antagonistas & inhibidores , Administración Oral , Disponibilidad Biológica , Humanos , Indoles/administración & dosificación , Indoles/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Amidas/química , Indoles/química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Perros , Evaluación Preclínica de Medicamentos , Indoles/síntesis química , Indoles/farmacocinética , Masculino , Ratones , Modelos Moleculares , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Anestésicos Intravenosos/química , Anestésicos Intravenosos/farmacología , Ésteres/química , Ésteres/farmacología , Fenoles/química , Fenoles/farmacología , Anestésicos Intravenosos/síntesis química , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Electroencefalografía/efectos de los fármacos , Ésteres/síntesis química , Infusiones Intravenosas/métodos , Masculino , Ratones , Ratones Mutantes , Fenoles/síntesis química , Propofol/farmacología , Ratas , Ratas Wistar , Receptores de GABA-A/efectos de los fármacos , Solubilidad , Relación Estructura-Actividad , Agua/químicaRESUMEN
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.
Asunto(s)
Aminoácidos/síntesis química , Aminoácidos/farmacología , Anestésicos Intravenosos/síntesis química , Anestésicos Intravenosos/farmacología , Fenoles/síntesis química , Fenoles/farmacología , Animales , Ésteres , Antagonistas de Receptores de GABA-A , Masculino , Ratones , Equilibrio Postural/efectos de los fármacos , Propofol/farmacología , Reflejo/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
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.