RESUMO
GPR84 is a medium chain free fatty acid-binding G-protein-coupled receptor associated with inflammatory and fibrotic diseases. As the only reported antagonist of GPR84 (PBI-4050) that displays relatively low potency and selectivity, a clear need exists for an improved modulator. Structural optimization of GPR84 antagonist hit 1, identified through high-throughput screening, led to the identification of potent and selective GPR84 inhibitor GLPG1205 (36). Compared with the initial hit, 36 showed improved potency in a guanosine 5'-O-[γ-thio]triphosphate assay, exhibited metabolic stability, and lacked activity against phosphodiesterase-4. This novel pharmacological tool allowed investigation of the therapeutic potential of GPR84 inhibition. At once-daily doses of 3 and 10 mg/kg, GLPG1205 reduced disease activity index score and neutrophil infiltration in a mouse dextran sodium sulfate-induced chronic inflammatory bowel disease model, with efficacy similar to positive-control compound sulfasalazine. The drug discovery steps leading to GLPG1205 identification, currently under phase II clinical investigation, are described herein.
Assuntos
Descoberta de Drogas/métodos , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Acetatos/química , Acetatos/farmacologia , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Células CACO-2 , Células Cultivadas , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is involved in the mediation of inflammatory responses. A class of azetidines was developed as potent FFA2 antagonists. Multiparametric optimization of early hits with moderate potency and suboptimal ADME properties led to the identification of several compounds with nanomolar potency on the receptor combined with excellent pharmacokinetic (PK) parameters. The most advanced compound, 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid 99 (GLPG0974), is able to inhibit acetate-induced neutrophil migration strongly in vitro and demonstrated ability to inhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specific epitope [AE], in a human whole blood assay. All together, these data supported the progression of 99 toward next phases, becoming the first FFA2 antagonist to reach the clinic.
Assuntos
Anti-Inflamatórios não Esteroides/metabolismo , Azetidinas/metabolismo , Butiratos/síntese química , Receptores de Superfície Celular/antagonistas & inibidores , Tiofenos/síntese química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Azetidinas/síntese química , Azetidinas/farmacocinética , Azetidinas/farmacologia , Butiratos/farmacocinética , Butiratos/farmacologia , Humanos , Doenças do Sistema Imunitário , Concentração Inibidora 50 , Transtornos Leucocíticos , Camundongos , Microssomos Hepáticos/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologiaRESUMO
A versatile approach for the enantioselective synthesis of functionalised beta-hydroxy N-acetylcysteamine thiol esters has been developed which allows the facile incorporation of isotopic labels. It has been shown that a remarkable reversal of selectivity occurs in the titanium mediated aldol reaction of acyloxazolidinone using either (S)- or (R)-tert-butyldimethylsilyloxybutanal. The aldol products are valuable intermediates in the synthesis of 4-hydroxy-6-substituted delta-lactones.