RESUMO
We have developed two parallel series, A and B, of CX3CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo[4,5-d]pyrimidine core structure, we were able to achieve compounds with high selectivity for CX3CR1 over the closely related CXCR2 receptor. The structure-activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with α-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds 18a and 24h. We show the preparation of the first potent and selective orally available CX3CR1 antagonists.
Assuntos
Esclerose Múltipla/tratamento farmacológico , Pirimidinas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Tiazóis/farmacologia , Amino Álcoois/síntese química , Amino Álcoois/farmacocinética , Amino Álcoois/farmacologia , Animais , Receptor 1 de Quimiocina CX3C , Células CACO-2 , Humanos , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacocinéticaRESUMO
Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer's disease. Synthetic methods, crystal structures, and structure-activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in Aß40 and Aß42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Aß was 40-50%, 1.5 h after oral dosing (100 µmol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Encéfalo/efeitos dos fármacos , Imidazóis/síntese química , Fragmentos de Peptídeos/metabolismo , Secretases da Proteína Precursora do Amiloide/química , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Ácido Aspártico Endopeptidases/química , Encéfalo/metabolismo , Linhagem Celular , Cristalografia por Raios X , Cães , Feminino , Cobaias , Humanos , Imidazóis/química , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Permeabilidade , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately potent inhibitor of cyclin-dependent kinase 5 (cdk5) from a HTS screen. The synthesis and SAR around this hit is described. The X-ray coordinates of ligand 4a with cdk5 are also reported, showing an unusual binding mode to the hinge region via a water molecule.
Assuntos
Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiofenos/química , Tiofenos/farmacologia , Cristalografia por Raios X , Quinase 5 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Proteínas do Tecido Nervoso/metabolismo , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Tiofenos/síntese químicaRESUMO
The evaluation of a series of aminoisoindoles as ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clinical candidate drug for Alzheimer's disease, (S)-32 (AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain reduction of Aß40, is discussed. Due to the basic nature of these compounds, they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 and (R)-41 showing large in vitro margins with BACE1 cell IC(50) values of 8.6 and 0.16 nM, respectively, and hERG IC(50) values of 16 and 2.8 µM, respectively. Several compounds were advanced into pharmacodynamic studies and demonstrated significant reduction of ß-amyloid peptides in mouse brain following oral dosing.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Indóis/síntese química , Pirimidinas/síntese química , Administração Oral , Alcinos/síntese química , Alcinos/farmacocinética , Alcinos/farmacologia , Amidas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Secretases da Proteína Precursora do Amiloide/química , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/química , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Cristalografia por Raios X , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Feminino , Transferência Ressonante de Energia de Fluorescência , Humanos , Ligação de Hidrogênio , Indóis/farmacocinética , Indóis/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Fragmentos de Peptídeos/metabolismo , Permeabilidade , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The syntheses and SAR of new series of beta-amyloid binding agents are reported. The effort to optimize signal-to-background ratios for these ligands are described. Compounds 8, 21 and 30 displayed desirable lipophilicity and pharmacokinetic properties. Compounds 8 and 21 were evaluated with in vitro autoradiographic studies and in vivo in APP/PS1 transgenic mice. It is shown that it was possible to increase the signal-to-background ratios compared to PIB 1, as demonstrated by compounds 8 and 21.