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1.
J Med Chem ; 58(5): 2326-49, 2015 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-25643210

RESUMO

High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.


Assuntos
Descoberta de Drogas , Hepatócitos/efeitos dos fármacos , Complexos Multiproteicos/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tioureia/análogos & derivados , Células Cultivadas , Hepatócitos/citologia , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Tioureia/química , Tioureia/farmacologia
2.
Bioorg Med Chem Lett ; 18(20): 5487-92, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18815031

RESUMO

An imidazole series of cyclin-dependent kinase (CDK) inhibitors has been developed. Protein inhibitor structure determination has provided an understanding of the emerging structure activity trends for the imidazole series. The introduction of a methyl sulfone at the aniline terminus led to a more orally bioavailable CDK inhibitor that was progressed into clinical development.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Imidazóis/química , Compostos de Anilina/química , Animais , Proteínas de Ciclo Celular/química , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Conformação Molecular , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 14(9): 2245-8, 2004 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-15081017

RESUMO

Exploration of SAR and optimisation of the imidazo[1,2-a]pyridine CDK inhibitors has lead to the discovery of novel, potent and selective inhibitors of the cyclin-dependent kinase CDK2. Understanding of SAR has identified positions of substitution, which allow modification of physical properties and offer the potential for in vivo optimisation.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 14(9): 2249-52, 2004 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-15081018

RESUMO

Modification of imidazo[1,2-a]pyridine CDK inhibitors lead to identification of less lipophilic imidazo[1,2-b]pyridazine series of CDK inhibitors. Although several equivalent compounds from these two series have similar structure and show similar CDK activity, the SAR of the two series differs significantly. Protein inhibitor structure determination has confirmed differences in binding mode and given some understanding of these differences in SAR. Potent and selective imidazo[1,2-b]pyridazine inhibitors of CDK2 have been identified, which show >1 microM plasma levels following a 2mg/kg oral dose to mice.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Piridazinas/química , Piridazinas/farmacologia , Animais , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/química , Camundongos , Modelos Moleculares , Piridazinas/sangue
5.
Bioorg Med Chem Lett ; 13(18): 3021-6, 2003 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12941325

RESUMO

High-throughput screening identified the imidazo[1,2-a]pyridine and bisanilinopyrimidine series as inhibitors of the cyclin-dependent kinase CDK4. Comparison of their experimentally-determined binding modes and emerging structure-activity trends led to the development of potent and selective imidazo[1,2-a]pyridine inhibitors for CDK4 and in particular CDK2.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Proteínas Proto-Oncogênicas , Piridinas/síntese química , Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Quinases relacionadas a CDC2 e CDC28/química , Cristalografia por Raios X , Quinase 2 Dependente de Ciclina , Quinase 4 Dependente de Ciclina , Quinases Ciclina-Dependentes/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ligação Proteica , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade
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