PMID- 29944371
OWN - NLM
STAT- MEDLINE
DCOM- 20190618
LR  - 20190618
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 61
IP  - 15
DP  - 2018 Aug 9
TI  - Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase 
      Inhibitors for the Treatment of Pain.
PG  - 6779-6800
LID - 10.1021/acs.jmedchem.8b00633 [doi]
AB  - Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived 
      neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are 
      known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and 
      TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been 
      clinically validated by the NGF antibody tanezumab, leading to significant 
      interest in the development of small molecule inhibitors of TrkA. Furthermore, 
      Trk inhibitors having an acceptable safety profile will require minimal brain 
      availability. Herein, we discuss the discovery of two potent, selective, 
      peripherally restricted, efficacious, and well-tolerated series of pan-Trk 
      inhibitors which successfully delivered three candidate quality compounds 10b, 
      13b, and 19. All three compounds are predicted to possess low metabolic clearance 
      in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus 
      addressing the potential clearance prediction liability associated with our 
      current pan-Trk development candidate PF-06273340.
FAU - Bagal, Sharan K
AU  - Bagal SK
AUID- ORCID: 0000-0003-0955-271X
AD  - Worldwide Medicinal Chemistry , Pfizer Worldwide R&D U.K. , The Portway Building, 
      Granta Park , Cambridge CB21 6GS , U.K.
FAU - Andrews, Mark
AU  - Andrews M
AD  - Pfizer Worldwide R&D U.K. , Sandwich , Kent CT13 9NJ , U.K.
FAU - Bechle, Bruce M
AU  - Bechle BM
AD  - Pfizer Worldwide R&D, Groton Laboratories , Eastern Point Road , Groton , 
      Connecticut 06340 , United States.
FAU - Bian, Jianwei
AU  - Bian J
AD  - Pfizer Worldwide R&D, Groton Laboratories , Eastern Point Road , Groton , 
      Connecticut 06340 , United States.
FAU - Bilsland, James
AU  - Bilsland J
AD  - Pfizer Worldwide R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 
      6GS , U.K.
FAU - Blakemore, David C
AU  - Blakemore DC
AD  - Worldwide Medicinal Chemistry , Pfizer Worldwide R&D U.K. , The Portway Building, 
      Granta Park , Cambridge CB21 6GS , U.K.
FAU - Braganza, John F
AU  - Braganza JF
AD  - Pfizer Worldwide R&D, La Jolla Laboratories , 10770 Science Center Drive , San 
      Diego , California 92121 , United States.
FAU - Bungay, Peter J
AU  - Bungay PJ
AD  - Pharmacokinetics, Dynamics & Metabolism , Pfizer Worldwide R&D U.K. , The Portway 
      Building, Granta Park , Cambridge CB21 6GS , U.K.
FAU - Corbett, Matthew S
AU  - Corbett MS
AD  - Pfizer Worldwide R&D, Groton Laboratories , Eastern Point Road , Groton , 
      Connecticut 06340 , United States.
FAU - Cronin, Ciaran N
AU  - Cronin CN
AD  - Pfizer Worldwide R&D, La Jolla Laboratories , 10770 Science Center Drive , San 
      Diego , California 92121 , United States.
FAU - Cui, Jingrong Jean
AU  - Cui JJ
AD  - Pfizer Worldwide R&D, La Jolla Laboratories , 10770 Science Center Drive , San 
      Diego , California 92121 , United States.
FAU - Dias, Rebecca
AU  - Dias R
AD  - Pfizer Worldwide R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 
      6GS , U.K.
FAU - Flanagan, Neil J
AU  - Flanagan NJ
AD  - Pfizer Worldwide R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 
      6GS , U.K.
FAU - Greasley, Samantha E
AU  - Greasley SE
AD  - Pfizer Worldwide R&D, La Jolla Laboratories , 10770 Science Center Drive , San 
      Diego , California 92121 , United States.
FAU - Grimley, Rachel
AU  - Grimley R
AD  - Pfizer Worldwide R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 
      6GS , U.K.
FAU - James, Kim
AU  - James K
AD  - Peakdale Molecular , Discovery Park House, Ramsgate Road , Sandwich CT13 9ND , 
      U.K.
FAU - Johnson, Eric
AU  - Johnson E
AD  - Pfizer Worldwide R&D, La Jolla Laboratories , 10770 Science Center Drive , San 
      Diego , California 92121 , United States.
FAU - Kitching, Linda
AU  - Kitching L
AD  - Pfizer Worldwide R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 
      6GS , U.K.
FAU - Kraus, Michelle L
AU  - Kraus ML
AD  - Pfizer Worldwide R&D, La Jolla Laboratories , 10770 Science Center Drive , San 
      Diego , California 92121 , United States.
FAU - McAlpine, Indrawan
AU  - McAlpine I
AD  - Pfizer Worldwide R&D, La Jolla Laboratories , 10770 Science Center Drive , San 
      Diego , California 92121 , United States.
FAU - Nagata, Asako
AU  - Nagata A
AD  - Pfizer Worldwide R&D, La Jolla Laboratories , 10770 Science Center Drive , San 
      Diego , California 92121 , United States.
FAU - Ninkovic, Sacha
AU  - Ninkovic S
AD  - Pfizer Worldwide R&D, La Jolla Laboratories , 10770 Science Center Drive , San 
      Diego , California 92121 , United States.
FAU - Omoto, Kiyoyuki
AU  - Omoto K
AD  - Worldwide Medicinal Chemistry , Pfizer Worldwide R&D U.K. , The Portway Building, 
      Granta Park , Cambridge CB21 6GS , U.K.
FAU - Scales, Stephanie
AU  - Scales S
AD  - Pfizer Worldwide R&D, La Jolla Laboratories , 10770 Science Center Drive , San 
      Diego , California 92121 , United States.
FAU - Skerratt, Sarah E
AU  - Skerratt SE
AD  - Worldwide Medicinal Chemistry , Pfizer Worldwide R&D U.K. , The Portway Building, 
      Granta Park , Cambridge CB21 6GS , U.K.
FAU - Sun, Jianmin
AU  - Sun J
AD  - Pfizer Worldwide R&D, Groton Laboratories , Eastern Point Road , Groton , 
      Connecticut 06340 , United States.
FAU - Tran-Dube, Michelle
AU  - Tran-Dube M
AD  - Pfizer Worldwide R&D, La Jolla Laboratories , 10770 Science Center Drive , San 
      Diego , California 92121 , United States.
FAU - Waldron, Gareth J
AU  - Waldron GJ
AD  - Pfizer Worldwide R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 
      6GS , U.K.
FAU - Wang, Fen
AU  - Wang F
AD  - Pfizer Worldwide R&D, La Jolla Laboratories , 10770 Science Center Drive , San 
      Diego , California 92121 , United States.
FAU - Warmus, Joseph S
AU  - Warmus JS
AD  - Pfizer Worldwide R&D, Groton Laboratories , Eastern Point Road , Groton , 
      Connecticut 06340 , United States.
LA  - eng
PT  - Journal Article
DEP - 20180727
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Ligands)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyridines)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - NH9L3PP67S (pyridine)
SB  - IM
MH  - Animals
MH  - *Drug Discovery
MH  - Humans
MH  - Ligands
MH  - Molecular Docking Simulation
MH  - Pain/*drug therapy
MH  - Protein Conformation
MH  - Protein Kinase Inhibitors/chemistry/pharmacokinetics/*pharmacology/therapeutic 
      use
MH  - Pyridines/chemistry/pharmacokinetics/pharmacology/therapeutic use
MH  - Rats
MH  - Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors/chemistry/metabolism
MH  - Solubility
MH  - Structure-Activity Relationship
MH  - Tissue Distribution
EDAT- 2018/06/27 06:00
MHDA- 2019/06/19 06:00
CRDT- 2018/06/27 06:00
PHST- 2018/06/27 06:00 [pubmed]
PHST- 2019/06/19 06:00 [medline]
PHST- 2018/06/27 06:00 [entrez]
AID - 10.1021/acs.jmedchem.8b00633 [doi]
PST - ppublish
SO  - J Med Chem. 2018 Aug 9;61(15):6779-6800. doi: 10.1021/acs.jmedchem.8b00633. Epub 
      2018 Jul 27.