title: 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.
abstract: 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.
authors: IRBM, Merck Research Laboratories Rome, Rome, Italy.
authors: Olaf
authors: O
authors: Kinzel
authors: Anna
authors: A
authors: Alfieri
authors: Sergio
authors: S
authors: Altamura
authors: Mirko
authors: M
authors: Brunetti
authors: Simone
authors: S
authors: Bufali
authors: Fabrizio
authors: F
authors: Colaceci
authors: Federica
authors: F
authors: Ferrigno
authors: Gessica
authors: G
authors: Filocamo
authors: Massimiliano
authors: M
authors: Fonsi
authors: Paola
authors: P
authors: Gallinari
authors: Savina
authors: S
authors: Malancona
authors: Jose Ignacio Martin
authors: JI
authors: Hernando
authors: Edith
authors: E
authors: Monteagudo
authors: Maria Vittoria
authors: MV
authors: Orsale
authors: Maria Cecilia
authors: MC
authors: Palumbi
authors: Vincenzo
authors: V
authors: Pucci
authors: Michael
authors: M
authors: Rowley
authors: Romina
authors: R
authors: Sasso
authors: Rita
authors: R
authors: Scarpelli
authors: Christian
authors: C
authors: Steinkühler
authors: Philip
authors: P
authors: Jones
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004285:Dogs; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C562332:8a-methyl-1,3-dioxo-2-(2-phenylcyclopropyl)-N-(1-phenyl-1H-pyrazol-5-yl)hexahydroimidazo(1,5-a)pyrazine-7(1H)-carboxamide; D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D007093:Imidazoles; D011719:Pyrazines