1351165-18-8Relevant articles and documents
Identification of MK-5710 ((8aS)-8a-methyl-1,3-dioxo-2-[(1S,2R)-2- phenylcyclo- propyl]-N-(1-phenyl-1H-pyrazol-5-yl)hexahydro-imidazo[1,5-a] pyrazine-7(1H)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies, Part 2
Kinzel, Olaf,Alfieri, Anna,Altamura, Sergio,Brunetti, Mirko,Bufali, Simone,Colaceci, Fabrizio,Ferrigno, Federica,Filocamo, Gessica,Fonsi, Massimiliano,Gallinari, Paola,Malancona, Savina,Hernando, Jose Ignacio Martin,Monteagudo, Edith,Orsale, Maria Vittoria,Palumbi, Maria Cecilia,Pucci, Vincenzo,Rowley, Michael,Sasso, Romina,Scarpelli, Rita,Steinkuehler, Christian,Jones, Philip
, p. 4429 - 4435 (2011/09/12)
The Hedgehog (Hh-) signaling pathway is a key developmental pathway which gets reactivated in many human tumors, and smoothened (Smo) antagonists are emerging as novel agents for the treatment of malignancies dependent on the Hh-pathway, with the most advanced compounds demonstrating encouraging results in initial clinical trials. A novel series of potent bicyclic hydantoin Smo antagonists was reported in the preceding article, these have been resolved, and optimized to identify potent homochiral derivatives with clean off-target profiles and good pharmacokinetic properties in preclinical species. While showing in vivo efficacy in mouse allograft models, unsubstituted bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-diones were shown to epimerize in plasma. Alkylation of the C-8 position blocks this epimerization, resulting in the identification of MK-5710 (47) which was selected for further development.
