RESUMO
A group of small molecule thienopyrimidine inhibitors of Notum Pectinacetylesterase are described. We explored both 2-((5,6-thieno[2,3-d]pyrimidin-4-yl)thio)acetic acids and 2-((6,7-thieno[3,2-d]pyrimidin-4-yl)thio)acetic acids. In both series, highly potent, orally active Notum Pectinacetylesterase inhibitors were identified.
Assuntos
Inibidores Enzimáticos/farmacologia , Esterases/antagonistas & inibidores , Fêmur/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Pirimidinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Esterases/metabolismo , Fêmur/anatomia & histologia , Fêmur/crescimento & desenvolvimento , Humanos , Camundongos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
A group of small molecule thienochromenes inhibitors of Notum Pectinacetylesterase are described. We developed SAR on three series based on carbon, oxygen and sulfur replacement of the 5-position. In each series, highly potent Notum Pectinacetylesterase inhibitors were identified.
Assuntos
Benzopiranos/química , Inibidores Enzimáticos/química , Esterases/antagonistas & inibidores , Animais , Benzopiranos/farmacocinética , Benzopiranos/uso terapêutico , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Esterases/metabolismo , Fêmur/fisiologia , Meia-Vida , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Osteoporose/tratamento farmacológico , Osteoporose/fisiopatologia , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The synthesis, SAR, and in vivo activity of inhibitors of delta-5 desaturase are described. Ring-constraint of the initial series provided access to a variety of in vitro active chemotypes, from which the indazole was selected. Examples from the indazole series displayed in vivo activity in reducing the enzymatic activity of liver delta-5 desaturase.
Assuntos
Amidas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Ácidos Graxos Dessaturases/antagonistas & inibidores , Síndrome Metabólica/tratamento farmacológico , Amidas/síntese química , Amidas/química , Animais , Dessaturase de Ácido Graxo Delta-5 , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ácidos Graxos Dessaturases/metabolismo , Humanos , Fígado/enzimologia , Síndrome Metabólica/enzimologia , Síndrome Metabólica/metabolismo , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The conformation-activity relationships for the biologically active polyketide, epothilone, have been determined. Computer-based molecular modeling and high field NMR techniques have provided the solution preferences for epothilones and. For the C1-C8 polypropionate region, two conformational families, conformers 1 and 2, have been identified as having significant populations in polar and non-polar solvents. In the C11-C15 region, additional flexibility was observed and two local conformations have been identified as important, conformers 3 and 4. Epothilone analogues with altered conformational profiles have been designed and synthesized. Conformational analysis and the results of biological assays have been correlated to provide increased understanding of the biologically active conformation for the epothilone class of natural product. Conformation-activity relationships have been shown to be an important complement to structure-activity data.
