title: Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain.
abstract: We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.
authors.affiliation: Departments of Medicinal Chemistry, Biological Chemistry, Pain & Migraine, Molecular Systems, and Structural Biology, Merck Research Laboratories , P.O. Box 4, West Point, Pennsylvania 19486, United States.
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Stachel
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Darrell A
authors.initials: DA
authors.lastname: Henze
authors.forename: Mike T
authors.initials: MT
authors.lastname: Rudd
authors.forename: Hua-Poo
authors.initials: HP
authors.lastname: Su
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Li
authors.forename: Kausik K
authors.initials: KK
authors.lastname: Nanda
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Egbertson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Manley
authors.forename: Kristen L G
authors.initials: KL
authors.lastname: Jones
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Brnardic
authors.forename: Ahren
authors.initials: A
authors.lastname: Green
authors.forename: Jay A
authors.initials: JA
authors.lastname: Grobler
authors.forename: Barbara
authors.initials: B
authors.lastname: Hanney
authors.forename: Michael
authors.initials: M
authors.lastname: Leitl
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Vandna
authors.initials: V
authors.lastname: Munshi
authors.forename: Dennis
authors.initials: D
authors.lastname: Murphy
authors.forename: Keith
authors.initials: K
authors.lastname: Rickert
authors.forename: Daniel
authors.initials: D
authors.lastname: Riley
authors.forename: Alicja
authors.initials: A
authors.lastname: Krasowska-Zoladek
authors.forename: Christopher
authors.initials: C
authors.lastname: Daley
authors.forename: Paul
authors.initials: P
authors.lastname: Zuck
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Kane
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bilodeau
mesh_terms: D000818:Animals; D059350:Chronic Pain / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics; D008024:Ligands; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D020917:Receptor, trkA / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000493:pharmacokinetics; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D007211:Indoles; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D054852:Small Molecule Libraries; D014230:Triazoles; D014508:Urea; D020917:Receptor, trkA