title: A novel inhibitor of active protein kinase G attenuates chronic inflammatory and osteoarthritic pain.
abstract: Activating PKG-1α induces a long-term hyperexcitability (LTH) in nociceptive neurons. Since the LTH correlates directly with chronic pain in many animal models, we tested the hypothesis that inhibiting PKG-1α would attenuate LTH-mediated pain. We first synthesized and characterized compound N46 (N-((3R,4R)-4-(4-(2-fluoro-3-methoxy-6-propoxybenzoyl)benzamido)pyrrolidin-3-yl)-1H-indazole-5-carboxamide). N46 inhibits PKG-1α with an IC50 of 7.5 nmol, was highly selective when tested against a panel of 274 kinases, and tissue distribution studies indicate that it does not enter the CNS. To evaluate its antinociceptive potential, we used 2 animal models in which the pain involves both activated PKG-1α and LTH. Injecting complete Freund's adjuvant (CFA) into the rat hind paw causes a thermal hyperalgesia that was significantly attenuated 24 hours after a single intravenous injection of N46. Next, we used a rat model of osteoarthritic knee joint pain and found that a single intra-articular injection of N46 alleviated the pain 14 days after the pain was established and the relief lasted for 7 days. Thermal hyperalgesia and osteoarthritic pain are also associated with the activation of the capsaicin-activated transient receptor protein vanilloid-1 (TRPV1) channel. We show that capsaicin activates PKG-1α in nerves and that a subcutaneous delivery of N46 attenuated the mechanical and thermal hypersensitivity elicited by exposure to capsaicin. Thus, PKG-1α appears to be downstream of the transient receptor protein vanilloid-1. Our studies provide proof of concept in animal models that a PKG-1α antagonist has a powerful antinociceptive effect on persistent, already existing inflammatory pain. They further suggest that N46 is a valid chemotype for the further development of such antagonists.
authors.affiliation: Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA, USA.
authors.forename: Ying-Ju
authors.initials: YJ
authors.lastname: Sung
authors.affiliation: Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA, USA.
authors.forename: Nelson
authors.initials: N
authors.lastname: Sofoluke
authors.affiliation: Department of Medicine, West Virginia University, Morgantown, WV, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Nkamany
authors.affiliation: Department of Medicine, Columbia University, New York, NY, USA.
authors.forename: Shixian
authors.initials: S
authors.lastname: Deng
authors.affiliation: Department of Medicine, Columbia University, New York, NY, USA.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Schrödinger Inc, New York, NY, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Greenwood
authors.affiliation: Schrödinger Inc, New York, NY, USA.
authors.forename: Ramy
authors.initials: R
authors.lastname: Farid
authors.affiliation: Department of Medicine, Columbia University, New York, NY, USA.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Landry
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Ambron
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use; D002908:Chronic Disease; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000627:therapeutic use; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005620:Freund's Adjuvant / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy; D008297:Male; D008958:Models, Molecular; D010003:Osteoarthritis / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology*; D010146:Pain / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013873:Thionucleotides / Q000627:therapeutic use; D013997:Time Factors
chemical_list: C582255:(N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl9tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-91,1'-biphenyl0-3-carboxamide; C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D011725:Pyridines; D013873:Thionucleotides; D000255:Adenosine Triphosphate; D005620:Freund's Adjuvant; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP