title: The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain.
abstract: The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially "druggable" point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340.
authors: Pfizer Global Research & Development , The Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, U.K.
authors: Sarah E
authors: SE
authors: Skerratt
authors: Pfizer Global Research & Development , Ramsgate Road, Sandwich CT13 9NJ, U.K.
authors: Mark
authors: M
authors: Andrews
authors: Pfizer Global Research & Development , The Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, U.K.
authors: Sharan K
authors: SK
authors: Bagal
authors: Pfizer Global Research & Development , The Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, U.K.
authors: James
authors: J
authors: Bilsland
authors: Pfizer Global Research & Development , Ramsgate Road, Sandwich CT13 9NJ, U.K.
authors: David
authors: D
authors: Brown
authors: Pfizer Global Research & Development , The Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, U.K.
authors: Peter J
authors: PJ
authors: Bungay
authors: Pfizer Global Research & Development , Ramsgate Road, Sandwich CT13 9NJ, U.K.
authors: Susan
authors: S
authors: Cole
authors: Pfizer Global Research & Development , Ramsgate Road, Sandwich CT13 9NJ, U.K.
authors: Karl R
authors: KR
authors: Gibson
authors: Pfizer Global Research & Development , Ramsgate Road, Sandwich CT13 9NJ, U.K.
authors: Russell
authors: R
authors: Jones
authors: Pfizer Global Research & Development , Ramsgate Road, Sandwich CT13 9NJ, U.K.
authors: Inaki
authors: I
authors: Morao
authors: Pfizer Global Research & Development , Ramsgate Road, Sandwich CT13 9NJ, U.K.
authors: Angus
authors: A
authors: Nedderman
authors: Pfizer Global Research & Development , The Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, U.K.
authors: Kiyoyuki
authors: K
authors: Omoto
authors: Pfizer Global Research & Development , Ramsgate Road, Sandwich CT13 9NJ, U.K.
authors: Colin
authors: C
authors: Robinson
authors: Pfizer Global Research & Development , Ramsgate Road, Sandwich CT13 9NJ, U.K.
authors: Thomas
authors: T
authors: Ryckmans
authors: Pfizer Global Research & Development , Ramsgate Road, Sandwich CT13 9NJ, U.K.
authors: Kimberly
authors: K
authors: Skinner
authors: Pfizer Global Research & Development , Ramsgate Road, Sandwich CT13 9NJ, U.K.
authors: Paul
authors: P
authors: Stupple
authors: Pfizer Global Research & Development , The Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, U.K.
authors: Gareth
authors: G
authors: Waldron
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D011494:Protein Kinases; C041311:tropomyosin kinase; C000620071:PF-06273340