title: Identification of MK-5710 ((8aS)-8a-methyl-1,3-dioxo-2-[(1S,2R)-2-phenylcyclopropyl]-N-(1-phenyl-1H-pyrazol-5-yl)hexahydroimid azo[1,5-a]pyrazine-7(1H)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies, part 1.
abstract: The Hedgehog (Hh-) signaling pathway is a key developmental pathway which controls patterning, growth and cell migration in most tissues, but evidence has accumulated showing that many human tumors aberrantly reactivate this pathway. Smoothened antagonists offer opportunities for the treatment of malignancies dependent on the Hh pathway, and the most advanced clinical candidates are demonstrating encourage initial results. A novel series of [6,5]-bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione smoothened antagonists has been identified, and the series has been extensively explored to ascertain the key detriments for activity, demonstrating that the trans-2-phenylcyclopropyl and hydantoin ring systems are critical for potency, while a variety of urea substituents can be tolerated. The combination of these optimal groups gives smoothened antagonists with activity in the low nanomolar range.
authors: IRBM, Merck Research Laboratories Rome, Rome, Italy. savinamal@libero.it
authors: Savina
authors: S
authors: Malancona
authors: Sergio
authors: S
authors: Altamura
authors: Gessica
authors: G
authors: Filocamo
authors: Olaf
authors: O
authors: Kinzel
authors: Jose Ignacio Martin
authors: JI
authors: Hernando
authors: Michael
authors: M
authors: Rowley
authors: Rita
authors: R
authors: Scarpelli
authors: Christian
authors: C
authors: Steinkühler
authors: Philip
authors: P
authors: Jones
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; 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