RESUMO
A novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure-activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid (32, BAF312, Siponimod), which has recently completed phase 2 clinical trials in patients with relapsing-remitting multiple sclerosis.
RESUMO
Various carboxylic acids, phosphonic acids, sulfonic acids, tetrazoles as well as sulfonylhydantoins were prepared as phosphate mimics of the chiral aminophosphate 1-P to act as agonists on the S1P(1) receptor. It was found that amino phosphonates and amino carboxylates are potent S1P(1) binders. beta-Amino acid 11 could be shown to reversibly reduce blood lymphocyte counts in rats after po administration.
Assuntos
Imunossupressores/química , Isoleucina/análogos & derivados , Fosfatos/química , Propilenoglicóis/química , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/análogos & derivados , Administração Oral , Aminoácidos/química , Animais , Cloridrato de Fingolimode , Imunossupressores/síntese química , Imunossupressores/farmacologia , Isoleucina/síntese química , Isoleucina/química , Isoleucina/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Fosforilação , Propilenoglicóis/farmacologia , Ratos , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/química , Esfingosina/farmacologiaRESUMO
High throughput screening and hit to lead optimization led to the identification of 'carene' as a promising scaffold showing selective S1P(1) receptor agonism. In parallel to this work we have established a pharmacophore model for the S1P(1) receptor highlighting the minimal structural requirement necessary for potent receptor agonism.
Assuntos
Monoterpenos/química , Pirazóis/química , Receptores de Lisoesfingolipídeo/agonistas , Monoterpenos Bicíclicos , Ensaios de Triagem em Larga Escala , Ligação de Hidrogênio , Pirazóis/síntese química , Pirazóis/farmacologia , Receptores de Lisoesfingolipídeo/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
FTY720 is an immunomodulator with demonstrated efficacy in a phase II trial of relapsing multiple sclerosis. FTY720-phosphate, the active metabolite generated upon phosphorylation in vivo, acts as a potent agonist on four of the five known sphingosine-1-phosphate (S1P(1)) receptors. AUY954, an aminocarboxylate analog of FTY720, is a low nanomolar, monoselective agonist of the S1P(1) receptor. Due to its selectivity and pharmacokinetic profile, AUY954 is an excellent pharmacological probe of S1P(1)-dependent phenomena. Oral administration of AUY954 induces a profound and reversible reduction of circulating lymphocytes and, in combination with RAD001 (Certican/Everolimus, an mTOR inhibitor), is capable of prolonging the survival of cardiac allografts in a stringent rat transplantation model. This demonstrates that a selective agonist of the S1P(1) receptor is sufficient to achieve efficacy in an animal model of transplantation.
Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Coração , Receptores de Lisoesfingolipídeo/agonistas , Tiofenos/farmacologia , beta-Alanina/análogos & derivados , Animais , Células CHO , Cricetinae , Cricetulus , Everolimo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Imunossupressores/farmacologia , Linfócitos/efeitos dos fármacos , Masculino , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Endogâmicos Lew , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Tiofenos/síntese química , Tiofenos/farmacocinética , Transplante Homólogo , beta-Alanina/síntese química , beta-Alanina/farmacocinética , beta-Alanina/farmacologiaRESUMO
In vivo phosphorylation of FTY720 (1) in rats and humans resulted exclusively in the biologically active (S)-configured enantiomer, which was proven by an ex vivo o-phthaldialdehyde derivatization protocol especially elaborated for phosphates of 1. Starting from the prochiral amino alcohol 1, racemic and enantiomerically pure phosphates of 1 were synthesized. Pure enantiomers were obtained after purification of a partially protected key intermediate on an enantioselective support. The absolute stereochemistry was determined by X-ray diffraction.
Assuntos
Adjuvantes Imunológicos/sangue , Organofosfatos/sangue , Propilenoglicóis/sangue , Animais , Células CHO , Cromatografia Líquida de Alta Pressão , Cricetinae , Cricetulus , Cristalografia por Raios X , Cloridrato de Fingolimode , Humanos , Masculino , Organofosfatos/síntese química , Organofosfatos/química , Organofosfatos/farmacologia , Fosforilação , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/análogos & derivados , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A modularly built bisubstrate inhibitor, the natural product pepticinnamin E (shown on the right) was sythesized for the first time. In the case of in vitro assays it inhibits the enzyme farnesyltransferase with respect to both the peptide substrate and farnesylpyrophosphate (KI = 30 and 8 µM, respectively). The inhibitory activity is decisively influenced by the central tripeptide unit and the absolute configuration of the non-proteinogenic amino acid incorporated therein.
RESUMO
The understanding of cellular communication pathways in molecular detail is an important goal of bioorganic research. The synthesis of analogues of active substances (e.g. 1) to study the regulation of muscle contraction or the specific lipid modification of representative peptides (â2) to investigate their subcellular, targeted transfer to intracellular membranes are examples of the capability of organic synthesis is in the research of biological signal transduction mechanisms.