RESUMO
We have published p53-MDM2 interaction inhibitors possessing a novel dihydroimidazothiazole scaffold. Although our lead compound 1 showed strong antitumor activity with single oral administration on a xenograft model using MV4-11 cells harboring wild-type p53, it needed a higher dose (200mg/kg) for distinct efficacy. We executed further optimization with the aim of improvement of potency and physicochemical properties. Thus optimal compounds were furnished by introducing fluorine moieties onto the phenyl ring at the C-6 position and the pyrrolidine part at the C-2 substituent; and modifying the terminal piperazine to 4,7-diazaspiro[2,5]octane variants. Furthermore, replacing 4-chlorophenyl on the C-5 position with pyridyl variant decreased nonspecific cytotoxicity significantly. Our exploration afforded DS-5272 indicating excellent antitumor efficacy from a dose of 25mg/kg on SJSA-1 xenografted models with high safety and good PK profiles, which has appropriate potency as a clinical candidate.
Assuntos
Antineoplásicos/síntese química , Neoplasias Ósseas/tratamento farmacológico , Imidazóis/síntese química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Sarcoma/tratamento farmacológico , Tiazóis/síntese química , Proteína Supressora de Tumor p53/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/farmacologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Flúor/química , Expressão Gênica , Humanos , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pirrolidinas/química , Sarcoma/genética , Sarcoma/metabolismo , Sarcoma/patologia , Tiazóis/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
With the aim of discovering potent inhibitors of the p53-MDM2 interaction and thus obtaining a potent anticancer drug, we have pursued synthesis and optimization of dihydroimidazothiazole derivatives, which have been discovered via scaffold hopping by mimicing the mode of interaction between MDM2 and Nutlins. Upon the discovery we encountered a problem involving the chemical instability of the scaffold, that is, susceptibility to oxidation which led to imidazothiazole. In order to solve this problem and to obtain further potent compounds, we executed medicinal research and thus furnished the optimal compounds by incorporating the methyl group onto the C-6 position to avoid the oxidation, and by modifying the C-2 moiety of the additional proline motif, which furnished high potency. The incorporation of the pyrrolidine moiety at the C-2 position raised another hydrophobic interaction site with MDM2 protein, which was generated by the induced-fitting observed by co-crystal structure analysis. These optimal molecules showed significant improvement in potency when compared with the early lead (+)-1 or Nutlin-3a.
Assuntos
Imidazóis/química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Tiazóis/química , Tiazóis/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Estereoisomerismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl)amino]methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 µg/mL; JP2, 462 µg/mL). Furthermore, this compound showed good oral bioavailability (F=54%) in monkeys.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/uso terapêutico , Integrina alfa4beta1/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Asma/imunologia , Disponibilidade Biológica , Brônquios/efeitos dos fármacos , Brônquios/imunologia , Linhagem Celular , Ácidos Cicloexanocarboxílicos/administração & dosagem , Ácidos Cicloexanocarboxílicos/farmacocinética , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Feminino , Haplorrinos , Humanos , Integrina alfa4beta1/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Pirrolidinas/administração & dosagem , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Solubilidade , Água/químicaRESUMO
We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53.
Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Imidazóis/síntese química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Tiazóis/síntese química , Proteína Supressora de Tumor p53/antagonistas & inibidores , Administração Oral , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Imidazóis/química , Imidazóis/farmacologia , Concentração Inibidora 50 , Ligação Proteica/efeitos dos fármacos , Tiazóis/química , Tiazóis/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
For the purpose of obtaining orally potent VLA-4 inhibitors, we have carried out structural modification of the (N'-phenylureido)phenyl group in compound 1, where the group was found to be attributed to poor pharmacokinetic profile in our previous research. Through modification, we have identified several compounds with both potent in vitro activity and improved oral exposure. In particular, compound 7e with 7-fluoro-2-(1-methyl-1H-indol-3-yl)-1,3-benzoxazolyl group as a novel replacement of the (N'-phenylureido)phenyl group significantly inhibited eosinophil infiltration into bronchoalveolar lavage fluid at 15mg/kg in an Ascaris-antigen-induced murine bronchial inflammatory model, and its efficacy was comparable to that of the anti-mouse α(4) antibody (R1-2).
Assuntos
Asma/tratamento farmacológico , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/uso terapêutico , Integrina alfa4beta1/antagonistas & inibidores , Administração Oral , Animais , Asma/imunologia , Brônquios/efeitos dos fármacos , Brônquios/imunologia , Lavagem Broncoalveolar , Linhagem Celular , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácidos Cicloexanocarboxílicos/farmacologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Relação Estrutura-AtividadeRESUMO
Preparations and in vitro antifungal activities of triazolopyridines, imidazopyridines, and a pyrazolopyridine were reported. Among those scaffolds, triazolopyridine was found to be the specific inhibitor of the synthesis of beta-1,6-glucan, an essential component of the fungal cell wall, and to show potent antifungal activities against several Candida species.
Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Imidazóis/química , Imidazóis/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Triazóis/química , Triazóis/farmacologia , beta-Glucanas/antagonistas & inibidores , beta-Glucanas/metabolismo , Antifúngicos/química , Antifúngicos/metabolismo , Candidíase/tratamento farmacológico , Estabilidade de Medicamentos , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Microssomos Hepáticos/metabolismo , Pirazóis/síntese química , Pirazóis/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Triazóis/síntese química , Triazóis/metabolismoRESUMO
Synthesis and in vitro antifungal evaluations of 1,3-benzoxazole-7-carbonitrile 3, 1,3-benzoxazole-4-carbonitrile 4, benzofuran 5, benzoxazine 7, and benzimidazole 8 were reported. Among them, 1,3-benzoxazole-4-carbonitrile was found to be a superior scaffold structure with moderate growth inhibition against Candida species. 1,3-Benzoxazole-4-carbonitrile 6 showed potent activity against Candida species compared to 5-desmethyl compound 4 and triazolopyridine 2. Compound 6 was efficiently prepared from versatile intermediate 24, which possessed six different substituents on the benzene ring. Conversion of benzene 24 into various 1,3-benzoxazole derivatives such as 2-aliphatic 34, 2-amino 35, and lactone 38 was demonstrated.
Assuntos
Antifúngicos/química , Benzimidazóis/química , Nitrilas/química , beta-Glucanas/metabolismo , Antifúngicos/síntese química , Antifúngicos/farmacologia , Compostos Bicíclicos com Pontes/química , Candida/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Nitrilas/síntese química , Nitrilas/farmacologia , beta-Glucanas/antagonistas & inibidoresRESUMO
We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.