RESUMO
Structure activity relationship (SAR) investigation of an oxadiazole based series led to the discovery of several potent FLAP inhibitors. Lead optimization focused on achieving functional activity while improving physiochemical properties and reducing hERG inhibition. Several compounds with favorable in vitro and in vivo properties were identified that were suitable for advanced profiling.
Assuntos
Inibidores da Proteína Ativadora de 5-Lipoxigenase/química , Proteínas Ativadoras de 5-Lipoxigenase/metabolismo , Oxidiazóis/química , Inibidores da Proteína Ativadora de 5-Lipoxigenase/metabolismo , Proteínas Ativadoras de 5-Lipoxigenase/química , Animais , Avaliação Pré-Clínica de Medicamentos , Canal de Potássio ERG1/antagonistas & inibidores , Canal de Potássio ERG1/metabolismo , Meia-Vida , Humanos , Concentração Inibidora 50 , Masculino , Microssomos Hepáticos/metabolismo , Oxidiazóis/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Solubilidade , Relação Estrutura-AtividadeRESUMO
A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor.
Assuntos
Inibidores da Proteína Ativadora de 5-Lipoxigenase/síntese química , Compostos de Boro/química , Carbamatos/química , Inibidores da Proteína Ativadora de 5-Lipoxigenase/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
A new class of chymase inhibitor featuring a benzimidazolone core with an acid side chain and a P(1) hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P(1) moiety. Replacement of the benzothiophene with different heterocyclic systems such as indoles and benzoisothiazole is feasible. Among the P(1) replacements, benzoisothiazole prevents the formation of GSH conjugate and an in silico analysis of oxidative potentials agreed with the experimental outcome.
Assuntos
Benzimidazóis/química , Quimases/antagonistas & inibidores , Inibidores de Proteases/química , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Sítios de Ligação , Quimases/metabolismo , Cristalografia por Raios X , Humanos , Interações Hidrofóbicas e Hidrofílicas , Oxirredução , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
Interleukin-2 inducible T-cell kinase (ITK) is a member of the Tec kinase family and is involved with T-cell activation and proliferation. Due to its critical role in acting as a modulator of T-cells, ITK inhibitors could provide a novel route to anti-inflammatory therapy. This work describes the discovery of ITK inhibitors through structure-based design where high-resolution crystal structural information was used to optimize interactions within the kinase specificity pocket of the enzyme to improve both potency and selectivity.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Motivos de Aminoácidos , Anti-Inflamatórios/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Cristalografia por Raios X/métodos , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Piridinas/química , Relação Estrutura-AtividadeRESUMO
An SAR study that identified a series of thienopyridine-based potent IkappaB Kinase beta (IKKbeta) inhibitors is described. With focuses on the structural optimization at C4 and C6 of structure 1 (Fig. 1), the study reveals that small alkyl and certain aromatic groups are preferred at C4, whereas polar groups with proper orientation at C6 efficiently enhance compound potency. The most potent analogues inhibit IKKbeta with IC50s as low as 40 nM, suppress LPS-induced TNF-alpha production in vitro and in vivo, display good kinase selectivity profiles, and are active in a HeLa cell NF-kappaB reporter gene assay, demonstrating that they directly interfere with the NF-kappaB signaling pathway.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridinas/química , Animais , Descoberta de Drogas , Células HeLa , Humanos , Quinase I-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Transdução de Sinais , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK.
Assuntos
Amidas/química , Benzimidazóis/química , Ácidos Carboxílicos/química , Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Microssomos Hepáticos/metabolismo , Proteínas Tirosina Quinases/química , Animais , Benzimidazóis/síntese química , Ácidos Carboxílicos/síntese química , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
A series of novel 12-membered ring macrolides was designed based on available information on structure-activity relationships and macrolide-ribosome interactions. Compounds with the desosamine and the anchor group properly attached to the 12-membered lactone ring exhibited improved activity against erythromycin-resistant organisms.