RESUMO
To obtain potent liver X receptor (LXR) agonists, a structure-activity relationship study was performed on a series of tert-butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improved the pharmacokinetic profile in mice, respectively. The obtained compound 32b increased blood ABCA1 mRNA expression without plasma TG elevation in both mice and cynomolgus monkeys.
Assuntos
Benzoatos/farmacologia , Descoberta de Drogas , Hidrocarbonetos Fluorados/farmacologia , Receptores Nucleares Órfãos/agonistas , Animais , Benzoatos/administração & dosagem , Benzoatos/química , Relação Dose-Resposta a Droga , Humanos , Hidrocarbonetos Fluorados/administração & dosagem , Hidrocarbonetos Fluorados/química , Receptores X do Fígado , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A novel class of NaV1.7 inhibitors has been identified by high-throughput screening followed by structure activity relationship studies. Among this series of compounds, piperidine 9o showed potent human and mouse NaV1.7 inhibitory activities with fair subtype selectivity over NaV1.5. Compound 9o successfully demonstrated analgesic efficacy in mice comparable to that of the currently used drug, mexiletine, but with an expanded central nervous system safety margin.
Assuntos
Descoberta de Drogas , Canal de Sódio Disparado por Voltagem NAV1.7/efeitos dos fármacos , Piperidinas/síntese química , Piperidinas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Humanos , Concentração Inibidora 50 , Mexiletina/química , Mexiletina/farmacologia , Camundongos , Estrutura Molecular , Piperidinas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/químicaRESUMO
We report synthesis and optimization of a series of (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of P1', P2' and P3 portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys.
Assuntos
Amidas/química , Piperazinas/síntese química , Piperidinas/química , Piperidinas/síntese química , Inibidores de Proteases/síntese química , Renina/antagonistas & inibidores , Administração Oral , Amidas/farmacocinética , Amidas/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Furosemida/farmacologia , Meia-Vida , Hipertensão/tratamento farmacológico , Macaca fascicularis , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , Ratos , Ratos Transgênicos , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure-activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h.
Assuntos
Anti-Hipertensivos/síntese química , Arritmias Cardíacas/prevenção & controle , Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Piperazinas/síntese química , Inibidores de Proteases/síntese química , Renina/antagonistas & inibidores , Administração Oral , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Pressão Arterial/efeitos dos fármacos , Feminino , Coração/fisiopatologia , Humanos , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Macaca fascicularis , Masculino , Técnicas de Cultura de Órgãos , Piperazinas/farmacocinética , Piperazinas/farmacologia , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Coelhos , Ratos , Renina/química , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
Introduction of the 2,2-dimethyl-4-phenylpiperazin-5-one scaffold into the P(3)-P(1) portion of the (2S,4S,5S)-5-amino-6-dialkylamino-4-hydroxy-2-isopropylhexanamide backbone dramatically increased the renin inhibitory activity without using the interaction to the S(3)(sp) pocket. Compound 31 exhibited >10,000-fold selectivity over other human proteases, and 18.5% oral bioavailability in monkey.
Assuntos
Amidas/química , Piperazinas/química , Renina/antagonistas & inibidores , Amidas/farmacologia , Aminação , Desenho de Fármacos , Hidroxilação , Metilação , Modelos Moleculares , Piperazina , Relação Estrutura-AtividadeRESUMO
Utilizing X-ray crystal structure analysis, (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides were designed and identified as renin inhibitors. The most potent compound 15 demonstrated favorable pharmacokinetic and pharmacodynamic profiles in rat.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Descoberta de Drogas , Piperazinas/farmacologia , Piperidinas/farmacologia , Renina/antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina/síntese química , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Haplorrinos , Humanos , Modelos Moleculares , Conformação Molecular , Piperazinas/síntese química , Piperazinas/química , Piperidinas/síntese química , Piperidinas/química , Renina/sangue , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
We have previously disclosed 1,2,4-oxadiazole derivative 3 as a potent S1P(3)-sparing S1P(1) agonist. Although compound 3 exhibits potent and manageable immunosuppressive efficacy in various in vivo models, recent studies have revealed that its 1,2,4-oxadiazole ring is subjected to enterobacterial decomposition. As provisions for unpredictable issues, a series of alternative compounds were synthesized on the basis of compound 3. Extensive SAR studies led to the finding of 1,3-thiazole 24c with the EC(50) value of 3.4 nM for human S1P(1), and over 5800-fold selectivity against S1P(3). In rat on host versus graft reaction (HvGR), the ID(50) value of 24c was determined at 0.07 mg/kg. The pharmacokinetics in rat and monkey is also reported. Compared to compound 3, 24c showed excellent stability against enterobacteria.
Assuntos
Piridinas/síntese química , Receptores de Lisoesfingolipídeo/agonistas , Tiazóis/química , Tiofenos/síntese química , Animais , Haplorrinos , Humanos , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , Tiazóis/farmacologia , Tiofenos/farmacologiaRESUMO
S1P(3)-sparing S1P(1) agonists have attracted attention as a suppressant of autoimmunity with reduced side effects. Our synthetic efforts and extensive SAR studies led to the discovery of 10b named CS-2100 with the EC(50) value of 4.0 nM for human S1P(1) and over 5000-fold selectivity against S1P(3). The in vivo immunosuppressive efficacy was evaluated in rats on host versus graft reaction and the ID(50) value was determined at 0.407mg/kg. The docking studies of CS-2100 with the homology model of S1P(1) and S1P(3) showed that the ethyl group on the thiophene ring of CS-2100 was sterically hindered by Phe263 in S1P(3), not in the case of Leu276 in S1P(1). This observation gives an explanation for the excellent S1P(3)-sparing characteristic of CS-2100.
Assuntos
Descoberta de Drogas , Oxidiazóis/síntese química , Receptores de Lisoesfingolipídeo/agonistas , Tiofenos/síntese química , Administração Oral , Animais , Ligação Competitiva , Humanos , Sistema Imunitário/efeitos dos fármacos , Imunossupressores/química , Imunossupressores/farmacologia , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/administração & dosagem , Oxidiazóis/farmacologia , Ratos , Relação Estrutura-Atividade , Tiofenos/administração & dosagem , Tiofenos/farmacologiaRESUMO
For the purpose of reducing the strong CYP3A4 inhibitory potency of diamide prodrug 4, cyclic prodrugs of tricyclic-based FBPase inhibitors were synthesized. Extensive SAR studies led to the discovery of pyridine-containing cyclic prodrug 20, which strongly inhibited glucose production in monkey hepatocytes and also showed weak CYP3A4 inhibitory potency.
Assuntos
Alanina/análogos & derivados , Inibidores do Citocromo P-450 CYP3A , Inibidores Enzimáticos/química , Organofosfonatos/química , Pró-Fármacos/química , Piridinas/química , Tiazóis/química , Alanina/síntese química , Alanina/química , Alanina/farmacologia , Animais , Células Cultivadas , Cristalografia por Raios X , Citocromo P-450 CYP3A/metabolismo , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Haplorrinos , Conformação Molecular , Organofosfonatos/síntese química , Organofosfonatos/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologiaRESUMO
An efficient and highly stereoselective total synthesis of the natural product (+/-)-welwitindolinone A isonitrile (1) is described. The bicyclo[4.2.0]octane core of 1 was established by a regio- and diastereoselective [2+2] ketene cycloaddition. The C12 quaternary center and vicinal stereogenic chlorine were installed in a single operation with excellent stereocontrol via a chloronium ion mediated semipinacol rearrangement. Described strategies for construction of the spiro-oxinole include a SmI2-LiCl mediated reductive cyclization and a novel anionic cyclization that simultaneously constructs the spiro-oxindole and vinyl isonitrile moieties.
Assuntos
Compostos Bicíclicos com Pontes/química , Alcaloides Indólicos/síntese química , Octanos/química , Ciclização , Alcaloides Indólicos/química , Indóis/síntese química , Indóis/química , Cetonas/síntese química , Cetonas/química , Conformação Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , EstereoisomerismoRESUMO
The deodorizing effect of the mushroom (Agaricus bisporus) extract on the malodor produced after garlic consumption was investigated using an electronic sensor and sensory evaluation measurements. Comparative gas chromatography analysis revealed that the quantity of methane- and allylthiols that were usually found after garlic solution rinse, significantly fell after mushroom extract rinsing. Furthermore, in-vitro analysis (mixing the garlic solution and mushroom extract) showed that the methanethiol reaction with the mushroom extract proceeded faster than that of the allylthiol. Ab initio calculations implicated an addition reaction as the possible mechanism between the thiol compounds and the polyphenols. In comparison to the methanethiol, the higher activation energy required by allylthiol for a feasible reaction path way with the model acceptor, o-quinone, is expected to contribute to the difference in the rate of the reaction.
Assuntos
Agaricus , Alho , Halitose/prevenção & controle , Odorantes/prevenção & controle , Administração Oral , Adolescente , Agaricus/química , Testes Respiratórios , Cromatografia Gasosa , Relação Dose-Resposta a Droga , Feminino , Alho/efeitos adversos , Alho/química , Halitose/induzido quimicamente , Humanos , Japão , Metano/análise , Fitoterapia/métodos , Extratos Vegetais/administração & dosagem , Análise de Componente Principal , Compostos de Sulfidrila/análise , Compostos de Sulfidrila/químicaRESUMO
[reaction: see text] Here we describe a miniature protein (1) that presents the cAMP-dependent protein kinase (PKA) recognition epitope found within the heat-stable Protein Kinase Inhibitor protein (PKI) and a miniature protein conjugate (1-K252a) in which 1 is joined covalently to the high-affinity but nonselective kinase inhibitor K252a. Miniature protein 1 recognizes PKA with an affinity that rivals that of PKI and, in the context of 1-K252a, leads to a dramatic increase in kinase specificity.
Assuntos
Carbazóis/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Carbazóis/química , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Alcaloides Indólicos , Estrutura Molecular , Especificidade por SubstratoRESUMO
A novel orally bioavailable renin inhibitor, DS-8108b (5), showing potent renin inhibitory activity and excellent in vivo efficacy is described. We report herein the synthesis and pharmacological effects of 5 including renin inhibitory activity in vitro, suppressive effects of ex vivo plasma renin activity (PRA) in cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in an animal model. Compound 5 demonstrated inhibitory activities toward human renin (IC50 = 0.9 nM) and human and monkey PRA (IC50 = 1.9 and 6.3 nM, respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in cynomolgus monkey on pretreatment with furosemide led to dose-dependent significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h.
RESUMO
Modulators of sphingosine phosphate receptor-1 (S1P(1)) have recently been focused as a suppressant of autoimmunity. We have discovered a 4-ethylthiophene-based S1P(1) agonist 1-({4-Ethyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methyl)azetidine-3-carboxylic acid (CS-2100, 8) showing potent S1P(1) agonist activity against S1P(3) and an excellent in vivo potency. We report herein the synthesis of CS-2100 (8) and pharmacological effects such as S1P(1) and S1P(3) agonist activity in vitro, peripheral blood lymphocyte lowering effects and the suppressive effects on adjuvant-induced arthritis and experimental autoimmune encephalomyelitis (EAE) in animal models. The pharmacokinetic data were also reported. CS-2100 (8) had >5000-fold greater agonist activity for human S1P(1) (EC(50); 4.0 nM) relative to S1P(3) (EC(50); >20,000 nM). Following administration of single oral doses of 0.1 and 1 mg/kg of CS-2100 (8) in rats, lymphocyte counts decreased significantly, with a nadir at 8 and/or 12 h post-dose and recovery to vehicle control levels by 24-48 h post-dose. CS-2100 (8) is efficacious in the adjuvant-induced arthritis model in rats (ID(50); 0.44 mg/kg). In the EAE model compared to the vehicle-treated group, significant decreases in the cumulative EAE scores were observed for 0.3 and 1 mg/kg CS-2100 (8) groups in mice. While CS-2100 (8) showed potent efficacy in various animal disease models, it was also revealed that the central 1,2,4-oxadiazole ring of CS-2100 (8) was decomposed by enterobacteria in intestine of rats and monkeys, implicating the latent concern about an external susceptibility in its metabolic process in the upcoming clinical studies.
Assuntos
Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Tiofenos/síntese química , Tiofenos/farmacologia , Administração Oral , Animais , Técnicas de Química Sintética , Desenho de Fármacos , Feminino , Meia-Vida , Humanos , Masculino , Camundongos , Oxidiazóis/administração & dosagem , Oxidiazóis/farmacocinética , Ratos , Tiofenos/administração & dosagem , Tiofenos/química , Tiofenos/farmacocinéticaRESUMO
BACKGROUND: Oncogenic RAS mutants such as v-Ha-RAS activate members of Rac/CDC42-dependent kinases (PAKs) and appear to contribute to the development of more than 30% of all human cancers. PAK1 activation is essential for oncogenic RAS transformation, and several chemical compounds that inhibit Tyr kinases essential for the RAS-induced activation of PAK1 strongly suppress RAS transformation either in cell culture or in vivo (nude mice). Although we have developed a cell-permeable PAK-specific peptide inhibitor called WR-PA18, so far no chemical (metabolically stable) compound has been developed that directly inhibits PAK1 in a highly selective manner. Thus, we have explored such a PAK1 inhibitor(s) among synthetic derivatives of an adenosine triphosphate antagonist. RESULTS: From the naturally occurring adenosine triphosphate antagonist K252a, we have developed two bulky derivatives, called CEP-1347 and KT D606 (a K252a dimer), which selectively inhibit PAKs or mixed-lineage kinases both in vitro and in cell culture and convert v-Ha-RAS-transformed NIH 3T3 cells to flat fibroblasts similar to the parental normal cells. Furthermore, these two K252a analogues suppress the proliferation of v-Ha-RAS transformants, but not the normal cells. CONCLUSION: These bulky adenosine triphosphate antagonists derived from K252a or related indolocarbazole compounds such as staurosporine would be potentially useful for the treatment of RAS/ PAK1-induced cancers, once their anti-PAK1 activity is significantly potentiated by a few additional chemical modifications at the sugar ring suggested in this paper.