RESUMO
The widespread emergence of antibiotic resistance, including multidrug resistance in Gram-negative (G-) bacterial pathogens, poses a critical challenge to the current antimicrobial armamentarium. Antibody-drug conjugates (ADCs), primarily used in anticancer therapy, offer a promising treatment alternative due to their ability to deliver a therapeutic molecule while simultaneously activating the host immune response. The Cloudbreak platform is being used to develop ADCs to treat infectious diseases, composed of a therapeutic targeting moiety (TM) attached via a noncleavable linker to an effector moiety (EM) to treat infectious diseases. In this proof-of-concept study, 21 novel dimeric peptidic molecules (TMs) were evaluated for activity against a screening panel of G- pathogens. The activities of the TMs were not impacted by existing drug resistance. Potent TMs were conjugated to the Fc fragment of human IgG1 (EM), resulting in 4 novel ADCs. These ADCs were evaluated for immunoprophylactic efficacy in a neutropenic mouse model of deep thigh infection. In colistin-sensitive infections, 3 of the 4 ADCs offered protection similar to that of therapeutically dosed colistin, while CTC-171 offered enhanced protection. The efficacy of these ADCs was unchanged in colistin-resistant infections. Together, these results indicate that the ADCs used here are capable of potent binding to G- pathogens regardless of lipopolysaccharide (LPS) modifications that otherwise lead to antibiotic resistance and support further exploration of ADCs in the treatment of infections caused by drug-resistant G- bacteria.
Assuntos
Colistina , Infecções por Bactérias Gram-Negativas , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Modelos Animais de Doenças , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Lipopolissacarídeos , CamundongosRESUMO
The polar-π effect on tetrazoles, medicinal chemistry isosteres of carboxylate, is tested by a Hammett pKa (microtitration) analysis over a series of 5-(m-terphenyl-2'-yl)-1H-tetrazoles. A comparison with m-terphenyl-2'-yl-carboxylic acids supports the isostere analogy also in response to environmental changes. Computational (B97D/def2TZVPPD) extension of the series plus a scan of solvents (vacuum to water) demonstrates the trend with the dielectric constant. The effect is energetically small but may make statistically significant contributions to the tetrazole pharmacological profile.
Assuntos
Ácidos Carboxílicos/química , Compostos de Terfenil/química , Tetrazóis/química , Ácidos/química , Modelos Moleculares , Compostos de Terfenil/síntese química , Tetrazóis/síntese química , TermodinâmicaRESUMO
The development of a series of novel 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. Optimization of microsomal clearance led to the identification of 9c, whose kinase selectivity is reported.
Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Relação Estrutura-AtividadeRESUMO
Gonadotropin releasing hormone (GnRH) plays an important role in the biology of reproduction. The use of GnRH receptor antagonists has been reported in the literature for the treatment of breast, ovarian, and prostate cancers. In this article, we report the synthesis, in vitro characterization, pharmacokinetics, and pharmacodynamics of an orally bioavailable, potent, small molecule GnRH receptor antagonist N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5-[3,3,6-trimthyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide (compound 1).
Assuntos
Indenos/síntese química , Morfolinas/síntese química , Pirimidinas/síntese química , Receptores LHRH/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Técnicas In Vitro , Indenos/química , Indenos/farmacologia , Fosfatos de Inositol/biossíntese , Masculino , Morfolinas/química , Morfolinas/farmacologia , Orquiectomia , Hipófise/metabolismo , Pirimidinas/química , Pirimidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testosterona/antagonistas & inibidores , Testosterona/metabolismoRESUMO
A series of pyridine ether PPAR agonists were synthesized through an ADDP and PS-PPh3 modified Mitsunobu protocol, which eliminated significant by-product formation. This method proved to be versatile, efficient and amenable to parallel synthesis.
RESUMO
Differences in regioselectivity were observed during the S(N)Ar reaction of amines with unsymmetrical 3,5-dichloropyrazines. This study revealed that when the 2-position of the pyrazine was occupied with an electron-withdrawing group (EWG), nucleophilic attack occurred preferentially at the 5-position. When the 2-position was substituted with an electron-donating group (EDG), nucleophilic attack occurred preferentially at the 3-position. These results are reported along with a computational rationale for the experimental observations based on the Fukui index at the reacting centers.
Assuntos
Aminas/química , Hidrocarbonetos Clorados/química , Pirazinas/química , Elétrons , Oxirredução , EstereoisomerismoRESUMO
A series of novel pyridine-2-propanoic acids was synthesized. A structure-activity relationship study of these compounds led to the identification of potent dual PPARalpha/gamma agonists with varied isoform selectivity. Based on the results of efficacy studies in diabetic (db/db) mice, and the desired pharmacokinetic parameters, compound (S)-13 was selected for further profiling.
Assuntos
Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Piridinas/química , Piridinas/farmacologia , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/patologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Masculino , Camundongos , Estrutura Molecular , PPAR alfa/metabolismo , PPAR gama/metabolismo , Piridinas/síntese química , Piridinas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
A series of novel pyridine-3-propanoic acids was synthesized. A structure-activity relationship study of these compounds led to the identification of potent dual PPARalpha/gamma agonists with varied isoform selectivity. Based on the results of efficacy studies in diabetic (db/db) mice, and the desired pharmacokinetic parameters, compounds (S)-14 and (S)-19 were selected for further profiling.