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1.
Bioorg Med Chem Lett ; 21(6): 1810-4, 2011 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-21324688

RESUMEN

A 3-amino-4-substituted pyrrolidine series of dipeptidyl peptidase IV (DPP-4) inhibitors was rapidly developed into a candidate series by identification of a polar valerolactam replacement for the lipophilic 2,4,5-trifluorophenyl pharmacophore. The addition of a gem-difluoro substituent to the lactam improved overall DPP-4 inhibition and an efficient asymmetric route to 3,4-diaminopyrrolidines was developed. Advanced profiling of a subset of analogs identified 5o with an acceptable human DPP-4 inhibition profile based on a rat PK/PD model and a projected human dose that was suitable for clinical development.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Piperidinas/uso terapéutico , Humanos , Modelos Moleculares , Piperidinas/química
2.
Bioorg Med Chem Lett ; 19(8): 2220-3, 2009 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-19285862

RESUMEN

A highly ligand efficient lead molecule was rapidly developed into a DPP-IV selective candidate series using focused small library synthesis. A significant hurdle for series advancement was genetic safety since some agents in this series impaired chromosome division that was detected using the in vitro micronucleus assay. A recently developed high-throughput imaging-based in vitro micronucleus assay enabled the identification of chemical space with a low probability of micronucleus activity. Advanced profiling of a subset within this space identified a compound with a clean safety profile, an acceptable human DPP-IV inhibition profile based on the rat PK/PD model and a projected human dose that was suitable for clinical development.


Asunto(s)
Diabetes Mellitus Tipo 2/enzimología , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/sangre , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Perros , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Fenetilaminas/química , Fenetilaminas/farmacología , Fenetilaminas/uso terapéutico , Piperidinas/química , Piperidinas/farmacología , Piperidinas/uso terapéutico , Ratas
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