Author/Authors :
Thomas D. Penning، نويسنده , , Gui-Dong Zhu، نويسنده , , Viraj B. Gandhi، نويسنده , , Jianchun Gong، نويسنده , , Sheela Thomas، نويسنده , , Wilfried Lubisch، نويسنده , , Roland Grandel، نويسنده , , Wolfgang Wernet، نويسنده , , Chang H. Park، نويسنده , , Elizabeth H. Fry، نويسنده , , Xuesong Liu، نويسنده , , Yan Shi، نويسنده , , Vered Klinghofer، نويسنده , , Eric F. Johnson، نويسنده , , Cherrie K. Donawho، نويسنده , , David J. Frost، نويسنده , , Velitchka Bontcheva-Diaz، نويسنده , , Jennifer J. Bouska، نويسنده , , Amanda M. Olson، نويسنده , , Kennan C. Marsh، نويسنده , , et al.، نويسنده ,
Abstract :
We have developed a series of cyclic amine-containing benzimidazole carboxamide poly(ADP-ribose)polymerase (PARP) inhibitors, with good PARP-1 enzyme potency, as well as cellular potency. These efforts led to the identification of a lead preclinical candidate, 10b, 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide (A-620223). 10b displayed very good potency against both the PARP-1 enzyme with a Ki of 8 nM and in a whole cell assay with an EC50 of 3 nM. 10b is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast xenograph model in combination with cisplatin.
Keywords :
PARP inhibitor , A-620223 , Benzimidazole carboxamide , Poly(ADP-ribose)polymerase
