RESUMO
Mutant isocitrate dehydrogenase 1 (IDH1) has been identified as an attractive oncology target for which >70% of grade II and III gliomas and â¼10% of acute myeloid leukemia (AML) harbor somatic IDH1 mutations. These mutations confer a neomorphic gain of function, leading to the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). We identified and developed a potent, selective, and orally bioavailable brain-penetrant tricyclic diazepine scaffold that inhibits mutant IDH1. During the course of in vitro metabolism studies, GSH-adduct metabolites were observed. The hypothesis for GSH-adduct formation was driven by the electron-rich nature of the tricyclic core. Herein, we describe our efforts to reduce the electron-rich nature of the core. Ultimately, a strategy focused on core modifications to block metabolic hot spots coupled with substitution pattern changes (C8 N â C linked) led to the identification of new tricyclic analogues with minimal GSH-adduct formation across species while maintaining an overall balanced profile.
RESUMO
A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.
RESUMO
The introduction of A ring pyrazole modification to the hydrocortisone C-21 heteroaryl thioethers generated compounds with excellent transrepression potency (IL-8 inhibition) compared to their hydrocortisone analogs. However, the transcriptional transactivation activity of these compounds were considerably higher than the corresponding hydrocortisone analogs. Among all the compounds evaluated, a quinoxaline thioether modification demonstrated the best overall in vitro separation.
Assuntos
Receptores de Glucocorticoides/efeitos dos fármacos , Esteroides/química , Sulfetos/química , Humanos , Hidrocortisona , Pirazóis/química , Relação Estrutura-Atividade , Sulfetos/farmacologia , Ativação Transcricional/efeitos dos fármacosRESUMO
The prednisolone C-21 heteroaryl thioethers have been synthesized and evaluated in cell based transrepression and transactivation assays. Most of the compounds demonstrated weak transactivational activity in both human and rat tyrosineaminotransferase functional assay while keeping potent anti-inflammatory activity. The benzimidazole thioether 7 exhibited comparable anti-inflammatory activity and improved safety profile compared to the classical oral steroid prednisolone.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Descoberta de Drogas , Receptores de Glucocorticoides/agonistas , Sulfetos/farmacologia , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Disponibilidade Biológica , Linhagem Celular , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Conformação Molecular , Ratos , Ratos Endogâmicos BN , Receptores de Glucocorticoides/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Sulfetos/administração & dosagem , Sulfetos/química , Tirosina Transaminase/metabolismoRESUMO
A series of C-21 mercapto derivatives of hydrocortisone have been synthesized and evaluated in cell based transrepression and transactivation assays. The benzothiazole derivative, compound 6 not only showed a dissociated profile in vitro functional assays but also a pharmacological profile in a Brown-Norway rat therapeutic index model of asthma that dissociated side effects (thymolysis) while maintaining efficacy against pulmonary inflammation and lung function.
Assuntos
Esteroides/farmacologia , Compostos de Sulfidrila/química , Administração por Inalação , Animais , Asma/tratamento farmacológico , Linhagem Celular , Descoberta de Drogas , Pulmão/efeitos dos fármacos , Ratos , Esteroides/administração & dosagem , Esteroides/química , Esteroides/uso terapêutico , Relação Estrutura-AtividadeRESUMO
A series of potent and orally bioavailable 3,4-diaminocyclobutenediones with various amide modifications and substitution on the left side phenyl ring were prepared and found to show significant inhibitory activities towards both CXCR2 and CXCR1 receptors.
Assuntos
Amidas/química , Ciclobutanos/síntese química , Diaminas/síntese química , Fenol/química , Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Administração Oral , Animais , Área Sob a Curva , Química Farmacêutica/métodos , Ciclobutanos/farmacologia , Diaminas/farmacologia , Desenho de Fármacos , Humanos , Inflamação , Cinética , Modelos Químicos , Ratos , Relação Estrutura-AtividadeRESUMO
A series of potent and selective 3,4-diamino-1,2,5-thiadiazoles were prepared and found to show excellent binding affinities towards CXCR2 receptor.
Assuntos
Diaminas/síntese química , Receptores de Interleucina-8B/antagonistas & inibidores , Tiadiazóis/síntese química , Diaminas/farmacologia , Humanos , Ligação Proteica , Receptores de Interleucina-8B/metabolismo , Relação Estrutura-Atividade , Tiadiazóis/farmacologiaRESUMO
A series of potent and orally bioavailable 3,4-diaminocyclobutenediones with various fluoroalkyl groups as alpha side chain were prepared and found to show significant improvements in the binding affinities towards both CXCR2 and CXCR1 receptors.
Assuntos
Ciclobutanos/síntese química , Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Administração Oral , Animais , Sítios de Ligação , Ciclobutanos/administração & dosagem , Ciclobutanos/metabolismo , Ligação Proteica , Ratos , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/metabolismoRESUMO
A series of novel and potent 3,4-diamino-2,5-thiadiazole-1-oxides were prepared and found to show excellent binding affinities for CXCR2 and CXCR1 receptors and excellent inhibitory activity of Gro-alpha and IL-8 mediated in vitro hPMN MPO release of CXCR2 and CXCR1 expressing cell lines. On the other hand, a closely related 3,4-diamino-2,5-thiadiazole-dioxide did not show functional activity despite its excellent binding affinities for CXCR2 and CXCR1 in membrane binding assays. A detailed SAR has been discussed in these two closely related structures.
Assuntos
Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Animais , Quimiocina CXCL1/química , Quimiocina CXCL1/farmacologia , Fatores Quimiotáticos/química , Fatores Quimiotáticos/farmacologia , Humanos , Interleucina-8/química , Interleucina-8/farmacologia , Cinética , Neutrófilos/efeitos dos fármacos , Neutrófilos/enzimologia , Óxidos/síntese química , Óxidos/química , Óxidos/farmacocinética , Óxidos/farmacologia , Peroxidase/metabolismo , Ratos , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/química , Tiadiazóis/farmacocinética , Tiadiazóis/farmacologiaRESUMO
Structure-activity studies on lead cyclobutenedione 3 led to the discovery of 4 (SCH 527123), a potent, orally bioavailable CXCR2/CXCR1 receptor antagonist with excellent cell-based activity. Compound 4 displayed good oral bioavailability in rat and may be a potential therapeutic agent for the treatment of various inflammatory diseases.