RESUMO
The design and synthesis of a novel class of 7-azaspiro[3.5]nonane GPR119 agonists are described. In this series, optimization of the right piperidine N-capping group (R2) and the left aryl group (R3) led to the identification of compound 54g as a potent GPR119 agonist. Compound 54g showed a desirable PK profile in Sprague-Dawley (SD) rats and a favorable glucose lowering effect in diabetic rats.
Assuntos
Alcanos/química , Desenho de Fármacos , Receptores Acoplados a Proteínas G/agonistas , Alcanos/síntese química , Alcanos/farmacocinética , Animais , Glicemia/análise , Linhagem Celular , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Teste de Tolerância a Glucose , Meia-Vida , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Microssomos Hepáticos/metabolismo , Piperidinas/química , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
We previously reported a novel series of 1H-pyrazolo[3,4-c]pyridine derivatives and the identification of compound 4b as a highly potent GPR119 agonist. However, the advancement of preclinical evaluations of compound 4b is expected to be difficult because of the compound's significantly poor aqueous solubility (0.71µM at pH6.8). In this article, we describe the further optimization of compound 4b focusing on the improvement of its aqueous solubility. Optimization of the central spacer, left-hand aryl group and right-hand piperidine N-capping group led to the identification of a potent GPR119 agonist, 3H-[1,2,3]triazolo[4,5-c]pyridine derivative 32o, with improved solubility (15.9µM at pH6.8).
Assuntos
Piridinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Triazóis/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
Design and synthesis of a novel class of 1H-pyrazolo[3,4-c]pyridine GPR119 receptor agonists are described. Lead compound 4 was identified through the ligand-based drug design approach. Modification of the left-hand aryl group (R(1)) and right-hand piperidine N-capping group (R(2)) led to the identification of compound 24 as a single-digit nanomolar GPR119 agonist.
Assuntos
Desenho de Fármacos , Piridinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
New clerodane-type diterpenes, designated as parvitexins A (1)-E (5), were isolated from the in vitro-cultured liverwort, Scapania parvitexta. These compounds were determined to be monoacetylated clerodane-type diterpenes based on spectroscopic evidence.
Assuntos
Diterpenos Clerodânicos/química , Hepatófitas/química , Diterpenos Clerodânicos/isolamento & purificação , Estrutura Molecular , Análise EspectralRESUMO
The production of specific IgE antibodies directed toward cedar pollen correlates well with the onset of allergic rhinitis; but the mechanisms of allergen recognition as nonself and Ig class switch to IgE by the immune system are still not fully understood. In the present study, we injected cedar pollen into mice through 4 different routes (intranasal (i.n.), intraperitoneal (i.p.), intravenous (i.v.), and subcutaneous (s.c.)) without adjuvant 1 to 3 times, and determined time-dependent changes in the total and specific serum IgE levels compared with those in the serum levels of other isotype Igs. After an i.p. or i.n. injection of allergen into the mice, they produced a 1.5-to 1.7-fold increase in total IgE, but none in IgG, IgM, or IgA antibodies in their serum, whereas an i.v. or s.c. injection of allergen was inactive as an inducer of total IgE antibodies. Upon a 2nd (s.c.) injection of the allergen into the i.p. or i.n. sensitized mice, a large amount of allergen-specific IgE antibodies was found in the serum. In the case of i.v. or s.c. sensitized mice, however, they produced total, but not specific, IgE antibodies; and a 3rd (s.c.) injection of the allergen resulted in a large amount of specific IgE antibodies in the serum. These results imply that resident cells at the i.p. or i.n. injection site may play a crucial role in the efficient production of total and specific IgE antibodies toward the allergen.
Assuntos
Alérgenos/administração & dosagem , Alérgenos/imunologia , Cedrus/imunologia , Imunoglobulina E/sangue , Pólen/imunologia , Administração Intranasal , Animais , Ensaio de Imunoadsorção Enzimática , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Injeções Intraperitoneais , Injeções Intravenosas , Injeções Subcutâneas , Japão , Camundongos , Camundongos Endogâmicos BALB CRESUMO
The new caffeic acid derivative, subulatin (1), was isolated from in vitro cultured liverworts, Jungermannia subulata, Lophocolea heterophylla, and Scapania parvitexta. The structure of 1 involved two caffeic acids, D-glucose, and 2-carboxy-6-(1,2-dihydroxy-ethyl)-4,5-dihydroxy-5,6-dihydro-4H-pyran. The connectivity of those and the absolute stereochemistry of 1 were elucidated on the basis of spectroscopic evidence. The antioxidative activity of 1 was comparable to that of alpha-tocopherol. (2'R)-Phaselic acid (2a) and (-)-9,2''-epiphylloyl-L-malic acid (4) were also isolated from J. subulata and L. heterophylla, respectively. A chiral HPLC analysis of the p-bromobenzoyl-malic acids derived from 2a showed that 2a from J. subulata was unusual (+)-trans-caffeoyl-D-malic acid.