title: The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: lead optimization.
abstract: This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: tony_siu@merck.com.
authors.forename: Tony
authors.initials: T
authors.lastname: Siu
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Sathyajith E
authors.initials: SE
authors.lastname: Kumarasinghe
authors.affiliation: Department of Structural Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Altman
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Katcher
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Northrup
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: White
authors.affiliation: Department of In Vitro Sciences, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Rosenstein
authors.affiliation: Department of Pharmacology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Anjili
authors.initials: A
authors.lastname: Mathur
authors.affiliation: Department of Drug Metabolism, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of In Vitro Sciences, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Chan
authors.affiliation: Department of Pharmacology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Bachman
authors.affiliation: Department of Basic Pharmaceutical Sciences, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Melaney
authors.initials: M
authors.lastname: Bouthillette
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Dinsmore
authors.affiliation: Department of Oncology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: C Gary
authors.initials: CG
authors.lastname: Marshall
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Young
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017434:Protein Structure, Tertiary; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D047428:Protein Kinase Inhibitors; D011728:Pyridones; D013449:Sulfonamides; D000255:Adenosine Triphosphate; D053614:Janus Kinase 2
keywords: JAK2; Kinase partition index; Kinase selectivity; Kinases; Ligand binding affinity; Molecular modeling; Water interaction