Wieslawa Maniara

TL;DR: Structural-activity relationship studies led to the discovery of a potent and specific Smoothened antagonist N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)biphenyl- 3-carboxamide (5m, NVP-LDE225), which is currently in clinical development.

TL;DR: A cell-based screen performed in the laboratories identified a new class of Hh pathway inhibitors, 1-amino-4-benzylphthalazines, that act via antagonism of the Smoothened receptor that displayed a good pharmacokinetic profile and also afforded tumor regression in a genetic mouse model of medulloblastoma.

TL;DR: Methyl substitution of the piperazine at the 2- and 5-positions markedly increased the potency of the lead compound (>1,000-fold) and oral bioavailability of the compounds in this series is good and is optimal when the 4-position of thepiperazine is substituted with an electron-poor benzoyl moiety.

TL;DR: This new agent combines high intrinsic potency and good pharmacokinetic properties resulting in excellent efficacy in preclinical rodent tumor models of medulloblastoma.

TL;DR: Efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c).