RESUMO
TAS-121 is a novel orally active selective covalent inhibitor of the mutant EGFR. We performed preclinical characterization of TAS-121 and compared its efficacy and selectivity for common EGFR mutations (Ex19del and L858R), first- and second- generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) resistance mutation (T790M), and uncommon mutations (G719X and L861Q) with those of other EGFR-TKIs. We also commenced investigation of the clinical benefits of TAS-121. The IC50 for intracellular EGFR phosphorylation was determined by using Jump-In GripTite HEK293 cells transiently transfected with EGFR expression vectors. Mouse xenograft models were used to evaluate the antitumor activity of TAS-121. TAS-121 potently inhibited common activating and resistance EGFR mutations to the same extent as another third-generation EGFR-TKI (osimertinib). In addition, TAS-121 showed equivalent inhibitory activity against some uncommon mutations such as G719X and L861Q. Furthermore, TAS-121 demonstrated greater selectivity for mutant EGFRs versus the wild-type EGFR compared with other EGFR-TKIs. Moreover, TAS-121 displayed antitumor activity in SW48 (EGFR G719S) and NCI-H1975 (EGFR L858R/T790M) xenograft models, and achieved an objective response in patients with NSCLC with EGFR mutations including G719A mutation. In conclusion, TAS-121 is a novel third-generation EGFR-TKI and demonstrates antitumor activities in patients with NSCLC expressing either common or uncommon EGFR mutations.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Quinolinas/farmacologia , Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Xenoenxertos , Humanos , Camundongos , Mutação/genéticaRESUMO
A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.
Assuntos
Amidas/síntese química , Benzofuranos/síntese química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Compostos de Espiro/síntese química , Transportadores de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Amidas/farmacologia , Animais , Benzofuranos/farmacologia , Encéfalo/metabolismo , Líquido Cefalorraquidiano/metabolismo , Estabilidade de Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Ratos , Compostos de Espiro/farmacologiaRESUMO
A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide derivatives were synthesized and profiled for NPY Y5 binding affinity, brain and CSF penetrability in rats, and susceptibility to human and mouse P-glycoprotein transporters in order to develop a PET ligand. Compound 12b exhibited an acceptable profile for a PET ligand, and [(11)C]12b was successfully utilized in clinical settings as a Y5 PET ligand.
Assuntos
Encéfalo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Ensaio Radioligante/métodos , Receptores de Neuropeptídeo Y/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular , Líquido Cefalorraquidiano/diagnóstico por imagem , Humanos , Ligantes , Camundongos , Plasma/diagnóstico por imagem , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis and structure-activity-relationships (SARs) of novel 2-(pyridine-2-yl)-1H-benzimidazole glucokinase activators are described. Systematic modification of benzimidazole lead 5a identified from a high-throughput screening led to the discovery of a potent and metabolically stable glucokinase activator 16p(R) with greater structural diversity from GKAs reported to date. The compound also demonstrated acute oral glucose lowering efficacy in rat OGTT model.
Assuntos
Benzimidazóis/síntese química , Glucoquinase/metabolismo , Sítio Alostérico , Animais , Benzimidazóis/farmacologia , Sítios de Ligação , Química Farmacêutica/métodos , Diabetes Mellitus Experimental/tratamento farmacológico , Desenho de Fármacos , Ativação Enzimática , Teste de Tolerância a Glucose , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Modelos Químicos , Conformação Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Spiroindoline urea derivatives, designed to act as NPY Y5 receptor antagonists, were synthesized and their structure-activity relationships were investigated. Of these derivatives, compound 3a showed good Y5 binding affinity with favorable pharmacokinetic properties. Compound 3a significantly inhibited bPP Y5 agonist-induced food intake in rats, and suppressed body weight gain in DIO mice.
Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Indóis/química , Indóis/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/metabolismo , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Disponibilidade Biológica , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Indóis/síntese química , Indóis/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/agonistas , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
Continuing medicinal chemistry studies to identify spiropiperidine-derived NPY Y5 receptor antagonists are described. Aryl urea derivatives of a variety of spiropiperidines were tested for their NPY Y5 receptor binding affinities. Of the spiropiperidines so far examined, spiro[3-oxoisobenzofurane-1(3H),4'-piperidine] was a useful scaffold for producing orally active NPY Y5 receptor antagonists. Oral administration of 5c significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 3mg/kg. In addition, this compound was efficacious in decreasing body weight in diet-induced obese mice.
Assuntos
Fármacos Antiobesidade/química , Piperidinas/química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Compostos de Espiro/química , Ureia/análogos & derivados , Administração Oral , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Ingestão de Alimentos , Humanos , Camundongos , Piperidinas/síntese química , Piperidinas/farmacologia , Ratos , Receptores de Neuropeptídeo Y/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Ureia/síntese química , Ureia/farmacologia , Redução de PesoRESUMO
A series of spiroindoline-3,4'-piperidine derivatives were synthesized and evaluated for their binding affinities and antagonistic activities at Y5 receptors. Potent Y5 antagonists were tested for their oral bioavailabilities and brain penetration in rats. Some of the antagonists showed good oral bioavailability and/or good brain penetration. In particular, compound 6e was orally bioavailable and brain penetrant, and oral administration of 6e inhibited bPP-induced food intake in rats with a minimum effective dose of 10mg/kg.
Assuntos
Química Farmacêutica/métodos , Indóis/administração & dosagem , Indóis/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/química , Administração Oral , Aminas/química , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Desenho de Fármacos , Concentração Inibidora 50 , Isocianatos/química , Modelos Químicos , Biblioteca de Peptídeos , Ratos , Ureia/químicaRESUMO
(9S)-9-(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one ((S)-1) was identified as a selective and orally active neuropeptide Y Y5 receptor antagonist. The structure-activity relationship for this structural class was investigated and showed that limited substitution on the phenyl ring was tolerated and that modification of the 4,4-dimethyl group of the cyclohexenone and the 3,3-dimethyl group of the xanthenone parts slightly improved potency. The plasma concentration-time profile after oral administration of (S)-1 in Sprague-Dawley (SD) rats showed significant in vivo racemization of (S)-1 and that (S)-1 is cleared much more quickly than (R)-1. The duration of (S)-1 in SD rats after oral administration of (RS)-1 racemate was twice as long as that following oral administration of (S)-1. The C max values of (S)-1 after administration of (S)-1 and (RS)-1 were comparable, and the brain to plasma ratio for (S)-1 was 0.34 in SD rats. In our acute D-Trp (34)NPY-induced food intake model, both (S)-1 and (RS)-1 showed potent and dose-dependent efficacy. Therefore, the use of (RS)-1 is suitable for studies that require sustained plasma exposure of (S)-1.
Assuntos
Cicloexanonas/administração & dosagem , Cicloexanonas/química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/metabolismo , Xantenos/administração & dosagem , Xantenos/química , Administração Oral , Ração Animal , Animais , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Cicloexanonas/síntese química , Cicloexanonas/metabolismo , Humanos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xantenos/síntese química , Xantenos/metabolismoRESUMO
A series of phenylpiperazine derivatives were synthesized and evaluated for their neuropeptide Y (NPY) Y5 receptor antagonistic activities. The benzindane portion of 2 was replaced by 1-phenylpiperazine, resulting in novel urea derivative 3f. Subsequent optimization of the phenylpiperazine template by substitution of the phenyl moiety resulted in a series of (2-methanesulfonamidephenyl)piperazine derivatives that showed potent binding affinity and antagonistic activity for the Y5 receptor.
Assuntos
Piperazinas/química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Humanos , Estrutura Molecular , Piperazinas/síntese química , Receptores de Neuropeptídeo Y/metabolismo , Relação Estrutura-AtividadeRESUMO
Novel arylpyrazole derivatives were synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Compound (-)-7, which features a novel chiral 2,3-dihydro-1H-cyclopenta[a]naphthalene moiety, showed good binding affinity and antagonistic activity for the Y5 receptor. After intracerebroventricular administration in SD rats, (-)-7 significantly inhibited food intake that was induced by the centrally administered Y5-preferring agonist, bovine pancreatic polypeptide, but had only a negligible effect on NPY-induced feeding.