RESUMO
The discovery, structure-activity relationships, and optimization of a novel class of fatty acid synthase (FASN) inhibitors is reported. High throughput screening identified a series of substituted piperazines with structural features that enable interactions with many of the potency-driving regions of the FASN KR domain binding site. Derived from this series was FT113, a compound with potent biochemical and cellular activity, which translated into excellent activity in in vivo models.
Assuntos
Ácido Graxo Sintases/antagonistas & inibidores , Piperazinas/química , Administração Oral , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ácido Graxo Sintases/metabolismo , Meia-Vida , Humanos , Malonil Coenzima A/metabolismo , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Piperazinas/farmacologia , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-AtividadeRESUMO
Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Piridinas/uso terapêutico , Quinolinas/uso terapêutico , Quinolonas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Feminino , Humanos , Isocitrato Desidrogenase/metabolismo , Camundongos Endogâmicos BALB C , Estrutura Molecular , Ligação Proteica , Piridinas/síntese química , Piridinas/metabolismo , Quinolinas/síntese química , Quinolinas/metabolismo , Quinolonas/síntese química , Quinolonas/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Isocitrato Desidrogenase/antagonistas & inibidores , Quinolonas/química , Quinolonas/farmacologia , Sítio Alostérico/efeitos dos fármacos , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Cristalografia por Raios X , Cães , Descoberta de Drogas , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Isocitrato Desidrogenase/química , Isocitrato Desidrogenase/genética , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Mutação Puntual , Quinolonas/farmacocinéticaRESUMO
A series of 5,6-diaryl-2-amino-pyrazines were prepared and found to have antagonist-like properties at the CB1 receptor. Subsequent SAR studies optimized both receptor potency and drug-like properties including solubility and Cytochrome-P450 inhibition potential. Optimized compounds were demonstrated to be inverse agonists and compared in vivo with rimonabant for their ability to inhibit food intake, to occupy central CB1 receptors and to influence hormonal markers associated with obesity.
Assuntos
Pirazinas/síntese química , Pirazinas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Animais , Glicemia/análise , Técnicas de Química Combinatória , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Modelos Animais de Doenças , Comportamento Alimentar/efeitos dos fármacos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Obesidade/metabolismo , Piperidinas/farmacologia , Pirazinas/sangue , Pirazóis/farmacologia , Ratos , Receptor CB1 de Canabinoide/sangue , Rimonabanto , Relação Estrutura-AtividadeRESUMO
The design, synthesis and structure-activity relationships of a novel series of CRF-1 receptor antagonist, the 1-aryl-4-alkylaminoisoquinolines, is described. The effects of substitution on the aromatic ring, the amino group and the isoquinoline core on CRF-1 receptor binding were investigated.
Assuntos
Desenho de Fármacos , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Ansiedade/tratamento farmacológico , Sítios de Ligação , Técnicas de Química Combinatória , Depressão/tratamento farmacológico , Humanos , Isoquinolinas/química , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
The design, synthesis, and structure-activity studies of a novel series of BK B(1) receptor antagonists based on a 1-benzylbenzimidazole chemotype are described. A number of compounds, for example, 38g, with excellent affinity for the cynomolgus macaque and rat bradykinin B(1) receptor were discovered.
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Animais , Benzimidazóis/química , Técnicas de Química Combinatória , Cães , Desenho de Fármacos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
A focused SAR exploration of the lead 4-aminoquinazoline TRPV1 antagonist 2 led to the discovery of compound 18. In rats, compound 18 is readily absorbed following oral dosing and demonstrates excellent in vivo potency and efficacy in an acute inflammatory pain model.
Assuntos
Aminoquinolinas/farmacologia , Química Farmacêutica/métodos , Canais de Cátion TRPV/antagonistas & inibidores , Aminoquinolinas/química , Animais , Cães , Desenho de Fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/química , Inflamação/tratamento farmacológico , Cinética , Modelos Químicos , Conformação Molecular , Dor/tratamento farmacológico , Preparações Farmacêuticas/química , Ratos , Canais de Cátion TRPV/químicaRESUMO
[reaction: see text] Novel and highly efficient syntheses of oxazolo[4,5-c]quinoline-4(5H)-ones (1) and thiazolo[4,5-c]quinoline-4(5H)-ones (2) from ethyl 2-chlorooxazole-4-carboxylate (4) and ethyl 2-bromo-5-chlorothiazole-4-carboxylate (13), respectively, are described.
RESUMO
The regiocontrolled synthesis of 2,5-disubstituted and 2,4,5-trisubstituted thiazoles from ethyl 2-bromo-5-chloro-4-thiazolecarboxylate 1 using sequential palladium-catalyzed coupling reactions is described. [reaction: see text]
Assuntos
Tiazóis/química , Tiazóis/síntese química , Catálise , Indicadores e Reagentes , Paládio/químicaRESUMO
[reaction: see text] By using a sequence of regiocontrolled halogenation and palladium-catalyzed coupling reactions, the synthesis of variously substituted oxazoles from ethyl 2-chlorooxazole-4-carboxylate (2) was accomplished. The methodology was applied to the synthesis of a series of 2,4-disubstituted, 2,5-disubstituted, and 2,4,5-trisubstituted oxazoles.
Assuntos
Oxazóis/síntese química , Alquilantes , Fatores Biológicos/síntese química , Halogênios/química , Oxazóis/química , Paládio/químicaRESUMO
The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund's adjuvant (CFA) induced chronic inflammatory pain after oral administration.