RESUMO
In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.
Assuntos
2-Aminopurina/química , 2-Aminopurina/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Purinas/química , Traumatismo por Reperfusão/enzimologia , Animais , Domínio Catalítico , Cães , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Haplorrinos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Purinas/farmacologia , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Starting from a phenol screening hit (6), three series of benzopyranone selective estrogen receptor modulators (SERMs) have been designed, synthesized, and analyzed for both estrogen receptor alpha binding affinity and in vitro activity in two cell assays. The lead compound identified, SP500263 (13), was more potent than raloxifene and tamoxifen in a cell-based assay measuring inhibition of interleukin-6 release.
Assuntos
Cumarínicos/farmacologia , Moduladores de Receptor Estrogênico/síntese química , Receptor alfa de Estrogênio/metabolismo , Interleucina-6/metabolismo , Piperidinas/farmacologia , Animais , Sítios de Ligação , Cumarínicos/síntese química , Estradiol/química , Estradiol/farmacologia , Antagonistas de Estrogênios/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Feminino , Interleucina-6/antagonistas & inibidores , Estrutura Molecular , Piperidinas/síntese química , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacologia , Tamoxifeno/química , Tamoxifeno/farmacologia , Células Tumorais CultivadasRESUMO
We determined the differential response of a novel SERM, SP500263, on estrogen receptor (ER) alpha and the more recently cloned ER-beta. Because of the high homology of amino acid residues in the ligand-binding domain of ER-alpha and ER-beta, we were not surprised to find that SP500263 binds to both ERs equally well. In contrast, SP500263 acts as a strong estrogen agonist in a strictly ER-alpha-specific manner in U2OS osteosarcoma cell lines blocking the production of interleukin (IL) 6 and granulocyte macrophage colony-stimulating factor. SP500263 also blocked IL-6 production in primary bone cells. The mechanism of this inhibition is different from the classic estrogen stimulation involving an estrogen response element (ERE). SP500263 does not activate gene expression through an ERE. In contrast to the results observed in U2OS cells, SP500263 acts as a strong estrogen antagonist in an MCF-7 breast cancer proliferation assay. Therefore, SP500263 is a member of a series of next-generation SERMs with functional selectivity toward ER-alpha and a mixed agonist/antagonist profile in a bone cell assay versus a breast cancer assay. The panel of assays described herein allow for the development of receptor-specific ligands that may be further developed into novel pharmaceuticals with an improved profile for the treatments of osteoporosis and breast cancer.
