RESUMO
New modifications on the C-8 4-aminobenzyl unit of the previously reported 3-alkyl-1,8-dibenzylxanthine inhibitors of cPEPCK are presented. The most active compound reported here is the 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid amide derivative 2 with an IC(50) of 0.29+/-0.08 microM. An X-ray analysis of a heteroaromatic sulfonamide is presented showing a new pi-pi interaction.
Assuntos
Citosol/enzimologia , Inibidores Enzimáticos/farmacologia , Fosfoenolpiruvato Carboxiquinase (GTP)/antagonistas & inibidores , Xantinas/farmacologia , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Xantinas/químicaRESUMO
The analysis of the X-ray structures of two xanthine inhibitors bound to PEPCK and a comparison to the X-ray structure of GTP bound to PEPCK are reported. The SAR at N-1, N-7 and developing SAR at C-8 are consistent with information gained from the X-ray structures of compounds 1 and 2 bound to PEPCK. Representative N-3 modifications of compound 2 that led to the discovery of 3-cyclopropylmethyl and its carboxy analogue as optimal N-3 groups are presented.
Assuntos
Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Xantinas/síntese química , Xantinas/farmacologia , Cristalografia por Raios X , Guanosina Trifosfato/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Fosfoenolpiruvato Carboxiquinase (ATP)/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The first non-substrate like inhibitors of human cytosolic phosphoenolpyruvate carboxykinase (PEPCK) competitive with GTP are reported. An effort to discover orally active compounds that improve glucose homeostasis in Type 2 diabetics by reversibly inhibiting PEPCK led to the discovery of 1-allyl-3-butyl-8-methylxanthine (5). We now report modifications at N-1 and C-8 that improved the in vitro activity of the initial xanthine HTS hit by 100-fold and a developing SAR for this class of inhibitor.
