title: Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479.
abstract: Use of the tools of SBDD including crystallography led to the discovery of novel and potent 6,5 heterobicyclic MEKi's [J. Med. Chem.2012, 55, 4594]. The core change from a 5,6 heterobicycle to a 6,5 heterobicycle was driven by the desire for increased structural diversity and aided by the co-crystal structure of G-925 [J. Med. Chem.2012, 55, 4594]. The key design feature was the shift of the attachment of the five-membered heterocyclic ring towards the B ring while maintaining the key hydroxamate and anilino pharamcophoric elements in a remarkably similar position as in G-925. From modelling, changing the connection point of the five membered ring heterocycle placed the H-bond accepting nitrogen within a good distance and angle to the Ser212 [J. Med. Chem.2012, 55, 4594]. The resulting novel 6,5 benzoisothiazole MEKi G-155 exhibited improved potency versus aza-benzofurans G-925 and G-963 but was a potent inhibitor of cytochrome P450's 2C9 and 2C19. Lowering the logD by switching to the more polar imidazo[1,5-a] pyridine core significantly diminished 2C9/2C19 inhibition while retaining potency. The imidazo[1,5-a] pyridine G-868 exhibited increased potency versus the starting point for this work (aza-benzofuran G-925) leading to deprioritization of the azabenzofurans. The 6,5-imidazo[1,5-a] pyridine scaffold was further diversified by incorporating a nitrogen at the 7 position to give the imidazo[1,5-a] pyrazine scaffold. The introduction of the C7 nitrogen was driven by the desire to improve metabolic stability by blocking metabolism at the C7 and C8 positions (particularly the HLM stability). It was found that improving on G-868 (later renamed GDC-0623) required combining C7 nitrogen with a diol hydroxamate to give G-479. G-479 with polarity distributed throughout the molecule was improved over G-868 in many aspects.
authors.affiliation: Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA, USA. Electronic address: kir@gene.com.
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Robarge
authors.affiliation: Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.affiliation: Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.affiliation: Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Ultsch
authors.affiliation: Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
authors.affiliation: Argenta, Discovery Services Charles River, 8-9 Spire Greene Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Heald
authors.affiliation: Argenta, Discovery Services Charles River, 8-9 Spire Greene Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Steve
authors.initials: S
authors.lastname: Price
authors.affiliation: Argenta, Discovery Services Charles River, 8-9 Spire Greene Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Hewitt
authors.affiliation: Argenta, Discovery Services Charles River, 8-9 Spire Greene Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Jackson
authors.affiliation: Argenta, Discovery Services Charles River, 8-9 Spire Greene Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Pascal
authors.initials: P
authors.lastname: Savy
authors.affiliation: Argenta, Discovery Services Charles River, 8-9 Spire Greene Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Brenda
authors.initials: B
authors.lastname: Burton
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA, USA.
authors.forename: Edna F
authors.initials: EF
authors.lastname: Choo
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA, USA.
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Boggs
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA, USA.
authors.forename: April
authors.initials: A
authors.lastname: Yang
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA, USA.
authors.forename: Xioaye
authors.initials: X
authors.lastname: Yang
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Baumgardner
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D045325:HCT116 Cells; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000596309:G-479 compound; D006571:Heterocyclic Compounds; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; C517813:imidazo(1,5-a)pyrazine; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Imidazo[1,5-a] pyrazine; Imidazo[1,5-a] pyridine; MEK inhibitors; Mitogen-activated protein kinase kinase inhibitors; Oncology; RAS signaling pathway; Structure based drug design (SBDD)