RESUMO
A series of 4-amino cyclohexanes and 4-substituted piperidines were prepared and evaluated for inhibition of DPP-4. Analog 20q displayed both good DPP-4 potency and selectivity against other proteases, while derivative 20k displayed long half life and modest oral bioavailability in rat. The most potent analog, 3-(5-aminocarbonylpyridyl piperidine 53j, displayed excellent DPP-4 activity with good selectivity versus other proline enzymes.
Assuntos
Cicloexanos/síntese química , Cicloexanos/farmacologia , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Animais , Disponibilidade Biológica , Cicloexanos/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Meia-Vida , Piperidinas/farmacocinética , RatosRESUMO
All reported GnRH receptor mutants (causing human hypogonadotropic hypogonadism) are misfolded proteins that cannot traffic to the plasma membrane. Pharmacoperones correct misfolding and rescue mutants, routing them to the plasma membrane where they regain function. Because pharmacoperones are often peptidomimetic antagonists, these must be removed for receptor function after rescue; in vivo this necessitates pulsatile pharmacoperone administration. As an antecedent to in vivo studies, we determined whether pharmacoperones need to be present at the time of synthesis or whether previously misfolded proteins could be refolded and rescued. Accordingly, we blocked either protein synthesis or intra-cellular transport. Biochemical and morphological studies using 12 mutants and 10 pharmacoperones representing three different chemical classes show that previously synthesized mutant proteins, retained by the quality control system (QCS), are rescued by pharmacoperones, showing that pharmacoperone administration in vivo likely need not consider whether the target protein is being synthesized at the time of drug administration.
Assuntos
Chaperonas Moleculares/farmacologia , Dobramento de Proteína , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores LHRH/metabolismo , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células COS , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Células HeLa , Humanos , Indóis/farmacologia , Inositol/farmacologia , Mimetismo Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Transporte Proteico/efeitos dos fármacos , Piridinas/farmacologia , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Receptores LHRH/química , Receptores LHRH/genética , TransfecçãoRESUMO
A series of beta-aminoacylpiperidines bearing various fused five-membered heterocyclic rings was synthesized as dipeptidyl peptidase IV inhibitors. Potent and relatively selective inhibition could be obtained, depending on choice of heterocycle, regioisomerism, and substitution. In particular, one analog (74, DPP-IV IC50=26 nM) exhibited good oral bioavailability and acceptable half-life in the rat, albeit with rather high clearance.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Piperidinas/síntese química , Piperidinas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Isoxazóis , Oxazóis , Piperidinas/química , Inibidores de Proteases/química , Pirazóis , TiazóisRESUMO
A diastereoselective synthesis was used to prepare a series of (3-substituted-cyclopentyl and -cyclohexyl)glycine pyrrolidides and thiazolidides. The three chiral centers were generated in an unambiguous, stereochemically defined manner. Inhibitory activity was dependent on the configuration at each stereocenter and on the nature of the 3-substituent. In the cyclopentylglycine pyrrolidide series, high potency against dipeptidyl peptidase IV and good selectivity could be achieved.