Development of a scalable chiral synthesis of MK-3281, an inhibitor of the hepatitis C virus NS5B polymerase
By Colarusso, Stefania; Conte, Immacolata; Di Filippo, Marcello; Ercolani, Caterina; MacKay, Angela C.; Palumbi, Maria…
By Kinzel, Olaf; Alfieri, Anna; Altamura, Sergio; Brunetti, Mirko; Bufali, Simone; Colaceci, Fabrizio; Ferrigno, Federica; Filocamo, Gessica; Fonsi, Massimiliano; Gallinari, Paola; et al
From Bioorganic & Medicinal Chemistry Letters (2011), 21(15), 4429-4435. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2011.06.023
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 compds. demonstrating encouraging results in initial clin. 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 derivs. with clean off-target profiles and good pharmacokinetic properties in preclin. 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 which was selected for further development.