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1.
Bioorg Med Chem ; 98: 117581, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38176113

RESUMO

Although KRAS protein had been classified as an undruggable target, inhibitors of KRAS G12C mutant protein were recently reported to show clinical efficacy in solid tumors. In our previous report, we identified 1-{2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one derivative (1) as a KRAS G12C inhibitor that covalently binds to Cys12 of KRAS G12C protein. Compound 1 exhibited potent cellular pERK inhibition and cell growth inhibition against a KRAS G12C mutation-positive cell line and showed an antitumor effect on subcutaneous administration in an NCI-H1373 (KRAS G12C mutation-positive cell line) xenograft mouse model in a dose-dependent manner. In this report, we further optimized the substituents on the quinazoline scaffold based on the structure-based drug design from the co-crystal structure analysis of compound 1 and KRAS G12C to enhance in vitro activity. As a result, ASP6918 was found to exhibit extremely potent in vitro activity and induce dose-dependent tumor regression in an NCI-H1373 xenograft mouse model after oral administration.


Assuntos
Neoplasias Pulmonares , Neoplasias , Humanos , Animais , Camundongos , Proteínas Proto-Oncogênicas p21(ras)/genética , Mutação , Relação Estrutura-Atividade , Neoplasias Pulmonares/tratamento farmacológico
2.
Bioorg Med Chem ; 71: 116949, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35926326

RESUMO

RAS protein plays a key role in cellular proliferation and differentiation. RAS gene mutation is a known driver of oncogenic alternation in human cancer. RAS inhibition is an effective therapeutic treatment for solid tumors, but RAS protein has been classified as an undruggable target. Recent reports have demonstrated that a covalent binder to KRAS protein at a mutated cysteine residue (G12C) is effective for the treatment of solid tumors. Here, we report a series of 1-{2,7-diazaspiro[3.5]nonan-2-yl}prop-2-en-1-one derivatives as potent covalent inhibitors against KRAS G12C identified throughout structural optimization of an acryloyl amine moiety to improve in vitro inhibitory activity. From an X-ray complex structural analysis, the 1-{2,7-diazaspiro[3.5]nonan-2-yl}prop-2-en-1-one moiety binds in the switch-II pocket of KRAS G12C. Further optimization of the lead compound (5c) led to the successful identification of 1-[7-[6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-[(1-methylpiperidin-4-yl)amino]quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-2-yl]prop-2-en-1-one (7b), a potent compound with high metabolic stabilities in human and mouse liver microsomes. Compound 7b showed a dose-dependent antitumor effect on subcutaneous administration in an NCI-H1373 xenograft mouse model.


Assuntos
Alcanos/farmacologia , Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Animais , Proliferação de Células , Humanos , Camundongos , Mutação , Neoplasias/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/farmacologia , Proteínas ras/genética , Proteínas ras/metabolismo
3.
Bioorg Med Chem ; 28(13): 115531, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32386953

RESUMO

The M3 muscarinic acetylcholine receptor (mAChR) is a member of the family of mAChRs, which are associated with a variety of physiological functions including the contraction of various smooth muscle tissues, stimulation of glandular secretion, and regulation of a range of cholinergic processes in the central nerve system. We report here the discovery and a comprehensive structure--activity relationships (SARs) study of novel positive allosteric modulators (PAMs) of the M3 mAChR through a high throughput screening (HTS) campaign. Compound 9 exhibited potent in vitro PAM activity towards the M3 mAChR and significant enhancement of muscle contraction in a concentration-dependent manner when applied to isolated smooth muscle strips of rat bladder. Compound 9 also showed excellent subtype selectivity over other subtypes of mAChRs including M1, M2, and M4 mAChRs, and moderate selectivity over the M5 mAChR, indicating that compound 9 is an M3-preferring M3/M5 dual PAM. Moreover, compound 9 displayed acceptable pharmacokinetics profiles after oral dosing to rats. These results suggest that compound 9 may be a promising chemical probe for the M3 mAChR for further investigation of its pharmacological function both in vitro and in vivo.


Assuntos
Agonistas Muscarínicos/síntese química , Fármacos Neuroprotetores/síntese química , Receptores Muscarínicos/metabolismo , Tiazóis/síntese química , Regulação Alostérica , Aminas/química , Animais , Células CHO , Sistema Nervoso Central/efeitos dos fármacos , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Agonistas Muscarínicos/farmacologia , Fármacos Neuroprotetores/farmacocinética , Piperidinas/química , Pirrolidinas/química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética
4.
Chem Pharm Bull (Tokyo) ; 67(8): 824-838, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366832

RESUMO

We synthesized and evaluated novel 5-[2-(thiophen-2-yl)propan-2-yl]-4H-1,2,4-triazole derivatives as 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors. Optimization of the thiophene ring and the substituents on the 1,2,4-triazole ring produced 3,4-dicyclopropyl-5-{2-[3-fluoro-5-(trifluoromethyl)thiophen-2-yl]propan-2-yl}-4H-1,2,4-triazole monohydrochloride (9a), which showed potent and selective inhibitory activity against human 11ß-HSD1. Compound 9a was also metabolically stable against human and mouse liver microsomes. Oral administration of 9a to diabetic ob/ob mice lowered corticosterone levels in adipose tissue, and thereby reduced plasma glucose and insulin levels in a dose-dependent manner.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Triazóis/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Administração Oral , Animais , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Células HEK293 , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Obesos , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/administração & dosagem , Triazóis/química
5.
Bioorg Med Chem ; 15(1): 160-73, 2007 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17064913

RESUMO

We found the novel selective and orally available non-amidine TF/FVIIa complex inhibitor 21e, 4-({[(1S)-(aminocarbonyl)-3-methylbutyl]amino}carbonyl)-2'-({[4- (aminomethyl)phenyl]amino}carbonyl)-4'-(methylamino)biphenyl-2- carboxylic acid. The derivatives were synthesized by conversions of the isobutyl moiety and the introduction of alkylamino groups to 4'-position of the central phenyl ring of compounds 2a and 2b reported previously. Some compounds show increased in vitro anti-TF/FVIIa and PT prolongation activities. Among them, compound 21e reached and sustained micromolar plasma concentration levels of up to 2h after oral administration in mice. Moreover, compound 21e did not prolong the bleeding time even at the highest dose level in cynomolgus monkeys, while PT was prolonged 3.7-fold increases at this dose.


Assuntos
Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Inibidores dos Fatores de Coagulação Sanguínea/síntese química , Fator VIIa/antagonistas & inibidores , Lipoproteínas/síntese química , Metilaminas/síntese química , Metilaminas/farmacologia , Tromboplastina/antagonistas & inibidores , Administração Oral , Animais , Sítios de Ligação , Compostos de Bifenilo/química , Inibidores dos Fatores de Coagulação Sanguínea/química , Inibidores dos Fatores de Coagulação Sanguínea/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligação de Hidrogênio , Ligantes , Lipoproteínas/química , Lipoproteínas/farmacologia , Macaca fascicularis , Masculino , Metilaminas/química , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Estrutura Secundária de Proteína , Sensibilidade e Especificidade , Estereoisomerismo , Relação Estrutura-Atividade
6.
Bioorg Med Chem ; 14(23): 7688-705, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16942884

RESUMO

Inhibition of tissue factor/factor VIIa complex (TF/FVIIa) is an attractive strategy for antithrombotic therapies. We began with an investigation of a non-amidine TF/FVIIa inhibitor based on a modification of amidine compound 1. Optimization of the substituents on the P1 phenyl portion of the compound 1 led to a neutral or less basic alternative for the 4-amidinophenyl moiety. By further optimization of the substituents on the central phenyl ring, a highly potent and selective TF/FVIIa inhibitor 17d was discovered.


Assuntos
Fator VIIa/antagonistas & inibidores , Fibrinolíticos/química , Tromboplastina/antagonistas & inibidores , Amidinas/química , Derivados de Benzeno , Humanos , Ligantes , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
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