Discovery of a Potent, Orally Bioavailable PI4KIIIß Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo.

The primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4- d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIß. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physicochemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound 22 was initially identified and profiled in vivo, before further modifications led to the discovery of 44 (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile. A co-crystal structure of 44 with PI4KIIIß was solved, confirming the binding mode of this class of inhibitor. The much-improved in vivo profile of 44 positions it as an ideal tool compound to further establish the link between PI4KIIIß inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo.

Clubbed [1,2,3] triazoles by fluorine benzimidazole: a novel approach to H37Rv inhibitors as a potential treatment for tuberculosis.

A Novel Clubbed [1,2,3] triazoles with fluorine benzimidazole series of H37Rv strain inhibitors, potentially useful for the treatment of tuberculosis is disclosed on the basis of promising results of preliminary antimicrobial study. Evaluation of the SAR of substitution within these series has followed the identification of a range of compounds. Some of the derivatives are under further evaluation showing better considerable activity compared to rifampin.