RESUMO
To examine the efficacy and safety of once-daily insulin degludec/insulin aspart (IDegAsp) or once-daily second-generation basal insulin analogs (insulin degludec and insulin glargine 300 units/mL) in insulin-naïve Japanese adults with type 2 diabetes in routine clinical practice. A 12-week multicenter, open-label, randomized, pilot study was performed in 52 subjects with type 2 diabetes treated with oral antidiabetic drugs (OADs). Subjects were randomized to once-daily IDegAsp (n = 26) or basal insulin (n = 26). The primary endpoint was percent change in HbA1c from baseline to week 12. Furthermore, it was analyzed post hoc in subgroups stratified by baseline HbA1c. During a follow-up period, percent change in HbA1c was not significantly different between the two groups (p = 0.161). Daily insulin doses and frequency of overall hypoglycemia were also similar in the two groups. In post hoc analyses, once-daily basal insulin was more effective than IDegAsp in subjects with HbA1c more than or equal to 8.5% (p < 0.05); however, in subjects with HbA1c less than 8.5%, once-daily IDegAsp showed a significant improvement in percent change in HbA1c at week 12, compared with basal insulin (p < 0.01). Although there was no apparent difference in the HbA1c-lowering effects between two groups, when compared in subjects with HbA1c less than 8.5%, once-daily IDegAsp showed a significant effect in comparison with once-daily basal insulin. These findings suggest that the baseline HbA1c level might provide the important information for choosing IDegAsp or basal insulin in patients insufficiently controlled with OADs. This trial was registered with UMIN (no. UMIN000035431).
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina Glargina/administração & dosagem , Insulina Glargina/efeitos adversos , Insulina de Ação Prolongada/administração & dosagem , Insulina de Ação Prolongada/efeitos adversos , Administração Oral , Adulto , Idoso , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Preparações de Ação Retardada , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
To identify an orally available drug candidate, a series of 3-benzoylaminophenylacetic acids were synthesized and evaluated as prostaglandin D(2) (PGD(2)) receptor antagonists. Some of the compounds tested were found to exhibit excellent inhibitory activity against cAMP accumulation in human platelet rich plasma (hPRP), which is one of the indexes of DP antagonism. The optimization process including improvement of the physicochemical properties such as solubility, which may result in an improved pharmacokinetic (PK) profile, is presented. Optimized compounds were studied for their pharmacokinetics and in vivo potential. A structure-activity relationship study is also presented. Some of the test compounds were found to have in vivo efficacy towards the inhibition of PGD(2)-induced and OVA-induced vascular permeability in guinea pig conjunctiva.
Assuntos
Fenilacetatos/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Administração Oral , Animais , Células CHO , Cricetinae , Cricetulus , Cobaias , Humanos , Modelos Moleculares , Fenilacetatos/química , Ratos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-AtividadeRESUMO
Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented.
Assuntos
Fármacos Anti-HIV/química , Benzoatos/química , Antagonistas dos Receptores CCR5 , Dicetopiperazinas/química , Administração Oral , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Benzoatos/síntese química , Benzoatos/farmacocinética , Dicetopiperazinas/síntese química , Dicetopiperazinas/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos , Cobaias , Haplorrinos , Humanos , Coelhos , Ratos , Receptores CCR5/metabolismo , Relação Estrutura-AtividadeRESUMO
Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate.
Assuntos
Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , Dicetopiperazinas/química , Compostos de Espiro/química , Administração Oral , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Linhagem Celular Tumoral , Dicetopiperazinas/síntese química , Dicetopiperazinas/farmacocinética , Dicetopiperazinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Proteína do Núcleo p24 do HIV/metabolismo , HIV-1/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Ratos , Receptores CCR5/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , EstereoisomerismoRESUMO
Using the previously reported novel spirodiketopiperazine scaffold, the design and synthesis of orally available CCR5 antagonists was undertaken. Compounds possessing a carboxylic acid function in the appropriate position showed improved oral exposure (AUC) relative to the initial chemical leads without reduction in the antagonist activity. The optimized compound 40 was found to show potent anti-HIV activity. Full details of structure-activity relationship (SAR) study are presented.
Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/farmacocinética , Antagonistas dos Receptores CCR5 , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/farmacocinética , Administração Oral , Animais , Fármacos Anti-HIV/química , Disponibilidade Biológica , Células CACO-2 , Humanos , Piperazinas/química , Ratos , Receptores CCR5/metabolismoRESUMO
Spirodiketopiperazine-based CCR5 antagonists, showing improved pharmacokinetic profiles without reduction in antagonist activity, were designed and synthesized. We also demonstrate the anti-HIV activity of a representative compound 12, as measured in a p24 assay.
Assuntos
Fármacos Anti-HIV/farmacocinética , Antagonistas dos Receptores CCR5 , Piperazinas/farmacocinética , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Proteína do Núcleo p24 do HIV/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Piperazinas/síntese química , Piperazinas/química , Ratos , Receptores CCR5/metabolismoRESUMO
Hydroxylated derivatives were designed and synthesized based on the information of oxidative metabolites. Compounds derived from beta-substituted (2R,3R)-2-amino-3-hydroxypropionic acid showed improved inhibitory activities against the binding of MIP-1alpha to human CCR5, compared with the non-hydroxylated derivatives and the other isomers.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Animais , Células CHO , Quimiocina CCL3 , Quimiocina CCL4 , Cromatografia Líquida de Alta Pressão , Técnicas de Química Combinatória , Cricetinae , Cricetulus , Desenho de Fármacos , Humanos , Hidroxilação , Técnicas In Vitro , Indicadores e Reagentes , Isomerismo , Proteínas Inflamatórias de Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Oxirredução , Ligação Proteica , RatosRESUMO
A series of 2-iminopiperidines fused to small-membered rings (Tables 1 and 2) were synthesised and biologically evaluated using an in vitro human nitric oxide synthase (NOS) inhibition assay. Fused bicyclic compounds 5-9 exhibited nearly the same potency as compound 1 in the hiNOS inhibition assay. Among these, the 1-methyl analogues 8 and 9 showed better isoform selectivity than their corresponding unsubstituted analogues 7 and 6, respectively. Compounds 5 and 6 were also evaluated by an in vivo NO accumulation assay in a mouse model. The discovery process of new chemical leads for an orally bioavailable inhibitor of human inducible NOS (iNOS) is reported. The structure-activity relationship (SAR) study and chemistry of these compounds are also reported.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Piperidinas/síntese química , Piperidinas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Desenho de Fármacos , Inibidores Enzimáticos/toxicidade , Humanos , Indicadores e Reagentes , Isoenzimas/antagonistas & inibidores , Cinética , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II , Proteínas Recombinantes/efeitos dos fármacos , Relação Estrutura-Atividade , Especificidade por Substrato , ômega-N-Metilarginina/farmacologiaRESUMO
Further chemical modification of 2-iminopiperidines fused to cyclopropane rings was performed. Optically active isomers 2 and 13 were synthesized and their biological activity was evaluated. Compound 2 exhibited greater potency and more isoform selectivity than enantiomer 13 in the iNOS inhibition assay. One of the gem-chlorines on the fused cyclopropane moiety of 2 was eliminated to produce 3, which showed reduced potency for iNOS inhibition, as well as 4 with an increased potency. The isoform selectivity of 4 was also much higher than that of 3. This was also true for the corresponding methyl derivatives 6-9. The structure-activity relationship (SAR) study and computer aided docking study of the most optimized structure 4 with human iNOS will also be reported.
Assuntos
Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Iminas/síntese química , Iminas/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Disponibilidade Biológica , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/toxicidade , Cristalografia por Raios X , Ciclopropanos/síntese química , Ciclopropanos/química , Ciclopropanos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/toxicidade , Humanos , Iminas/química , Iminas/toxicidade , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , ômega-N-Metilarginina/farmacologiaRESUMO
The process of discovery and biological evaluation of alpha,beta-unsaturated cyclic amidines, as selective inhibitors of inducible nitric oxide synthase (iNOS), is reported. Dihydropyridin-2(1H)-imines and 1,5,6,7-tetrahydro-2H-azepin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide synthase inhibition assay. Compounds 1, 5, 6, 8-12 and 16 exhibited potent inhibition of iNOS. Among these, compounds 6, 7, 10, 11 and 16 showed 5- to 19-fold isoform selectivity. Compounds 1, 6, 10, 11 and 16 also showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 6 showed excellent bioavailability (BA) in rats when administered orally. Full details are presented here, including the structure-activity relationship (SAR) studies, the chemistry of these compounds, and the pharmacokinetic data and the computer-aided docking study of 10 with hiNOS.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Iminas/síntese química , Iminas/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Animais , Disponibilidade Biológica , Simulação por Computador , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Indicadores e Reagentes , Injeções Intravenosas , Isoenzimas/antagonistas & inibidores , Cinética , Espectrometria de Massas , Camundongos , Modelos Moleculares , Conformação Molecular , Nitratos/metabolismo , Óxido Nítrico Sintase Tipo II , Ratos , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
Dihydropyridin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide inhibition assay. Compounds 1, 4, 5 and 7-11 exhibited potent activity in the inducible nitric oxide (iNOS) inhibition assay. Of these 5, 6, 9 and 10 showed 5- to 11-fold increases in isoform selectivity. Compounds 1, 5, 9 and 10 showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 5 also showed good bioavailability (BA) when given orally.