RESUMO
A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
Assuntos
Antineoplásicos/farmacologia , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 2/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Quinina/análogos & derivados , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Linfoma Cutâneo de Células T/metabolismo , Linfoma Cutâneo de Células T/patologia , Modelos Moleculares , Estrutura Molecular , Quinina/síntese química , Quinina/química , Quinina/farmacologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Solubilidade , Relação Estrutura-AtividadeRESUMO
Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield.
Assuntos
Proteína ADAM17/antagonistas & inibidores , Inibidores Enzimáticos/química , Proteína ADAM17/metabolismo , Administração Tópica , Animais , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Ácidos Hidroxâmicos/química , Camundongos , Camundongos Pelados , Microssomos Hepáticos/metabolismo , Oxazolona/toxicidade , Psoríase/tratamento farmacológico , Psoríase/patologia , Dermatopatias/induzido quimicamente , Dermatopatias/prevenção & controle , Dermatopatias/veterinária , Solubilidade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.
Assuntos
Proteína ADAM17/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/química , Proteína ADAM17/metabolismo , Administração Tópica , Humanos , Psoríase/tratamento farmacológico , Psoríase/enzimologiaRESUMO
Peroxisome proliferator activated receptors (PPARs) have been shown to have critical roles in fatty acid oxidation, triglyceride synthesis, and lipid metabolism - making them an important target in drug discovery. Here we describe the in silico design, synthesis and in vitro characterisation of a novel series of 2,5-disubstituted indoles as PPARα/γ dual agonists. PPAR activation assays are performed with known agonists diazabenzene (WY14.643), aminopyridine (BRL49653) and bisaryl (L165.041), as positive controls. All the indole compounds synthesized are found to be active PPARα and PPARγ agonists, with particular efficacy from those with 2-naphthylmethyl substitution. This is a useful demonstration of a new de novo design methodology implemented by the protobuild program and its ability to rapidly produce novel modulators for a well characterized drug target.
Assuntos
Biologia Computacional/métodos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Síndrome Metabólica/tratamento farmacológico , PPAR alfa/agonistas , PPAR gama/agonistas , Software , Indóis/química , Ligantes , Modelos Moleculares , Estrutura MolecularRESUMO
Tetradecylthioacetic acid (TTA) is a modified fatty acid that appears to improve insulin sensitivity, lower blood lipid levels, enhance fatty acid oxidation and promote anti-inflammatory action in vivo, through mechanisms partly dependent upon peroxisome proliferator-activated receptors (PPARs). In order to improve the biological efficacy of TTA as a PPAR agonist, two novel phospholipid analogue lyso tetradecylthioacetyl-L-alpha-phosphatidylcholine and di-tetradecylthioacetyl-L-alpha-phosphatidylglycerol have been developed. Here we report on the syntheses of these novel phospholipids and their relative potential to act as PPAR agonists in vitro, in comparison to TTA and other positive controls.
Assuntos
PPAR alfa/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Fosfolipídeos/síntese química , Fosfolipídeos/farmacologia , Sulfetos/química , Sulfetos/farmacologia , Animais , Linhagem Celular , Humanos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fosfolipídeos/metabolismo , Ratos , Ratos WistarRESUMO
Tetradecylthioacetic acid (TTA) 1 is a peroxisome proliferator-activated receptor (PPAR) agonist found to improve insulin sensitivity, lower blood lipid levels, enhance fatty acid oxidation, and promote anti-inflammation in vivo. In an attempt to enhance these properties, two key thioether fatty acid (Thefa) lipids, ditetradecylthioacetyl phosphatidylcholine 2 and tritetradecylthioacetyl glycerol 3, are synthesized and administered po to male Wistar rats at two different doses to study and compare metabolic outcomes relative to the administration of 1 alone after 6 days. Liposomal formulations of 1 and 2 are also prepared to evaluate acute metabolic responses (at 3 h) post i.v. injection. Across all metrics measured, 1-induced responses post po administration are in line with previous data. Responses induced from 3 are mostly equivalent to 1-induced responses. By contrast, 2-induced responses almost always outperform those of 1 and 3. Therefore, 2 may represent a new lead for the treatment of metabolic syndrome.