RESUMO
The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of phospho-RSK levels in HepG2 cells and tumor xenografts.
Assuntos
Descoberta de Drogas , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Combinatória , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Células Hep G2 , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Pirimidinas/química , Bibliotecas de Moléculas Pequenas , Relação Estrutura-AtividadeRESUMO
In the course of our study on selective nonsteroidal mineralocorticoid receptor (MR) antagonists, a series of novel benzoxazine derivatives possessing an azole ring as the core scaffold was designed for the purpose of attenuating the partial agonistic activity of the previously reported dihydropyrrol-2-one derivatives. Screening of alternative azole rings identified 1,3-dimethyl pyrazole 6a as a lead compound with reduced partial agonistic activity. Subsequent replacement of the 1-methyl group of the pyrazole ring with larger lipophilic side chains or polar side chains targeting Arg817 and Gln776 increased MR binding activity while maintaining the agonistic response at the lower level. Among these compounds, 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (37a) showed highly potent in vitro activity, high selectivity versus other steroid hormone receptors, and good pharmacokinetic profiles. Oral administration of 37a in deoxycorticosterone acetate-salt hypertensive rats showed a significant blood pressure-lowering effect with no signs of antiandrogenic effects.
Assuntos
Descoberta de Drogas , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Oxazinas/farmacologia , Pirazóis/farmacologia , Receptores de Mineralocorticoides/metabolismo , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/química , Antagonistas de Androgênios/farmacologia , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Células COS , Chlorocebus aethiops , Cristalografia por Raios X , Acetato de Desoxicorticosterona , Relação Dose-Resposta a Droga , Humanos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Masculino , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/química , Modelos Moleculares , Estrutura Molecular , Oxazinas/administração & dosagem , Oxazinas/química , Pirazóis/administração & dosagem , Pirazóis/química , Ratos , Ratos Wistar , Receptores de Mineralocorticoides/agonistas , Relação Estrutura-AtividadeRESUMO
Dihydrofuran-2-one and dihydropyrrol-2-one derivatives were identified as novel, potent and selective mineralocorticoid receptor (MR) antagonists by the structure-based drug design approach utilizing the crystal structure of MR/compound complex. Introduction of lipophilic substituents directed toward the unfilled spaces of the MR and identification of a new scaffold, dihydropyrrol-2-one ring, led to potent in vitro activity. Among the synthesized compounds, dihydropyrrol-2-one 11i showed an excellent in vitro activity (MR binding IC50=43nM) and high selectivity over closely related steroid receptors such as the androgen receptor (AR), progesterone receptor (PR) and glucocorticoid receptor (GR) (>200-fold for AR and PR, 100-fold for GR).
Assuntos
Benzofuranos/química , Benzoxazinas/química , Desenho de Fármacos , Antagonistas de Receptores de Mineralocorticoides/síntese química , Pirróis/química , Animais , Células COS , Chlorocebus aethiops , Cristalografia por Raios X , Concentração Inibidora 50 , Antagonistas de Receptores de Mineralocorticoides/química , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Mineralocorticoid receptor (MR) blockade has come into focus as a promising approach for the treatment of cardiovascular diseases such as hypertension and congestive heart failure. In order to identify a novel class of nonsteroidal MR antagonists that exhibit significant potency and good selectivity over other steroidal hormone receptors, we designed a novel series of benzoxazin-3-one derivatives and synthesized them from 6-(7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-2H-1,4-benzoxazin-3(4H)-one (1a), high-throughput screening (HTS) hit compound. Our design was based on a crystal structure of an MR/compound complex and a docking model. In the course of lead generation from 1a, a 1,2-diaryl framework was characterized as a key structure with high binding affinity. On the basis of scaffold hopping and optimization studies, benzoxazin-3-one derivatives possessing 1-phenyl-3-trifluoromethylpyrazol-5-yl moiety at the 6-position were identified as a novel series of potent and selective MR antagonists. Among these compounds, 6-[1-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2H-1,4-benzoxazin-3(4H)-one (14n) showed highly potent activity and good selectivity and also exhibited a significant antihypertensive effect in deoxycorticosterone acetate-salt hypertensive rats. On the basis of these results, compound 14n was progressed for further pharmacological evaluation.
Assuntos
Anti-Hipertensivos/síntese química , Benzoxazinas/síntese química , Antagonistas de Receptores de Mineralocorticoides , Pirazóis/síntese química , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Benzoxazinas/farmacocinética , Benzoxazinas/farmacologia , Ligação Competitiva , Cristalografia por Raios X , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Proteica , Pirazóis/farmacocinética , Pirazóis/farmacologia , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
The synthesis and biological evaluation of novel tetrahydroisoquinoline, tetrahydroquinoline, and tetrahydroazepine antagonists of the human and rat H(3) receptors are described. The substitution around these rings as well as the nature of the substituent on nitrogen is explored. Several compounds with high affinity and selectivity for the human and rat H(3) receptors are reported.