RESUMO
Initial evaluation of a series 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines revealed a C(1') carboxamide was preferred for sub-micromolar in vitro potency against IGF-1R. Subsequent solution stability studies with 1 revealed a susceptibility toward acid-induced intramolecular cyclization with the C(1') carboxamide. Herein, we describe several successful approaches toward generating both potent and acid-stable inhibitors of IGF-1R within the 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine template.
Assuntos
Ácidos/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Pirróis/químicaRESUMO
Exploration of the SAR around a series of 3,5-disubstituted-1H-pyrrolo[2,3-b]pyridines led to the discovery of novel pyrrolopyridine inhibitors of the IGF-1R tyrosine kinase. Several compounds demonstrated nanomolar potency in enzyme and cellular mechanistic assays.
Assuntos
Inibidores de Proteínas Quinases/química , Piridinas/química , Pirróis/química , Receptor IGF Tipo 1/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Receptor IGF Tipo 1/metabolismo , Relação Estrutura-AtividadeRESUMO
The SAR of C5' functional groups with terminal basic amines at the C6 aniline of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines is reported. Examples demonstrate potent inhibition of IGF-1R with 1000-fold selectivity over JNK1 and 3 in enzymatic assays.
Assuntos
MAP Quinase Quinase 4/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Modelos Moleculares , Pirimidinas/química , Pirróis/química , Relação Estrutura-AtividadeRESUMO
The evaluation of a series of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines as inhibitors of the IGF-1R (IGF-IR) receptor tyrosine kinase is reported. Examples demonstrate nanomolar potencies in in vitro enzyme and mechanistic cellular assays as well as promising in vivo pharmacokinetics in rat.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Descoberta de Drogas , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/química , RatosRESUMO
Aniline 'headgroups' were synthesized and incorporated into an alkynyl thienopyrimidine series of EGFR and ErbB-2 inhibitors. Potent inhibition of enzyme activity and cellular proliferation was observed. In certain instances, protein binding was reduced and oral exposure was found to be somewhat improved relative to compounds containing the reference aniline.
Assuntos
Compostos de Anilina/síntese química , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Receptor ErbB-2/antagonistas & inibidores , Administração Oral , Compostos de Anilina/administração & dosagem , Compostos de Anilina/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Receptores ErbB/metabolismo , Inibidores do Crescimento/administração & dosagem , Inibidores do Crescimento/síntese química , Inibidores do Crescimento/farmacologia , Humanos , Camundongos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Receptor ErbB-2/metabolismoRESUMO
A novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 receptor tyrosine kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.
Assuntos
Antineoplásicos/química , Receptores ErbB/antagonistas & inibidores , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Administração Oral , Animais , Camundongos , Farmacocinética , Pirimidinas/síntese química , Pirrolidinas/síntese química , Relação Estrutura-AtividadeRESUMO
The optimization of imidazo[1,2-a]pyridine inhibitors as potent and selective inhibitors of IGF-1R is presented. Further optimization of oral exposure in mice is also discussed. Detailed selectivity, in vitro activity, and in vivo PK profiles of an optimized compound is also highlighted.
Assuntos
Química Farmacêutica/métodos , Piridinas/química , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/química , Administração Oral , Compostos de Anilina/química , Animais , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Conformação Molecular , Piridinas/síntese química , Piridinas/farmacologia , Receptor de Insulina/metabolismoRESUMO
A synthetic route to bisanilino-1H-pyrrolo[2,3-d]pyrimidines has been discovered, wherein the C(6)-chloride reactivity is necessarily enhanced via reversible acid-catalyzed internal activation of the pyrimidine ring by a C(1')-carboxamide moiety. Subsequent selective nucleophilic displacements at C(6) and C(1') constitute a one-pot tandem protocol for the rapid assembly of bisanilino-1H-pyrrolo[2,3-d]pyrimidines.
Assuntos
Amidas/química , Química Orgânica/métodos , Pirimidinas/química , Pirróis/química , Carbono/química , Catálise , Cloretos/química , Desenho de Fármacos , Modelos QuímicosRESUMO
A novel series of pyrazolo[1,5-b]pyridazines have been synthesized and identified as cyclin dependant kinase inhibitors potentially useful for the treatment of solid tumors. Modification of the hinge-binding amine or the C(2)- and C(6)-substitutions on the pyrazolopyridazine core provided potent inhibitors of CDK4 and demonstrated enzyme selectivity against VEGFR-2 and GSK3beta.
Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/síntese química , Piridazinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta , Modelos Moleculares , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism. This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ that demonstrates efficacy in a rat model of arthritis.
Assuntos
Artrite Experimental/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Quinazolinonas/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/enzimologia , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/enzimologia , Células Cultivadas , Colágeno/toxicidade , Cristalografia por Raios X , Modelos Animais de Doenças , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratos , Ratos Endogâmicos Lew , Distribuição TecidualRESUMO
[reaction: see text] A convergent synthesis of substituted pyrazolo[1,5-a]pyridines has been achieved either via a regioselective [3 + 2] cycloaddition of N-aminopyridines with alkynes or by thermal cyclization of disubstituted azirines. Subsequent palladium-catalyzed introduction of pyridines or de novo synthesis of pyrimidines affords inhibitors of p38 kinase.
Assuntos
Inibidores de Proteínas Quinases/química , Pirazóis/química , Piridinas/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Cristalografia por Raios X , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Anilinoalkynylpyrimidines were prepared and evaluated as dual EGFR/ErbB2 kinase inhibitors. A preference was found for substituted phenyl and heteroaromatic rings attached to the alkyne. In addition, the presence of a potential hydrogen bond donor appended to this ring was favored. Selected molecules in the series demonstrated some activity against human tumor cell lines.