Literature DB >> 27660691

Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design.

Spencer B Jones1, Lance A Pfeifer1, Thomas J Bleisch1, Thomas J Beauchamp1, Jim D Durbin1, V Joseph Klimkowski1, Norman E Hughes1, Christopher J Rito1, Yen Dao1, Joseph M Gruber1, Hai Bui1, Mark G Chambers1, Srinivasan Chandrasekhar1, Chaohua Lin1, Denis J McCann1, Daniel R Mudra1, Jennifer L Oskins1, Craig A Swearingen1, Kannan Thirunavukkarasu1, Bryan H Norman1.   

Abstract

In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC50 = 2 nM), PK properties, and a robust PK/PD relationship.

Entities:  

Keywords:  Autotaxin; LPA; osteoarthritis; tool molecule

Year:  2016        PMID： 27660691      PMCID： PMC5018868          DOI： 10.1021/acsmedchemlett.6b00207

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  16 in total

1.  Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation.

Authors:  Harald M H G Albers; Anping Dong; Laurens A van Meeteren; David A Egan; Manjula Sunkara; Erica W van Tilburg; Karianne Schuurman; Olaf van Tellingen; Andrew J Morris; Susan S Smyth; Wouter H Moolenaar; Huib Ovaa
Journal:  Proc Natl Acad Sci U S A       Date:  2010-04-01       Impact factor: 11.205

2.  A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation.

Authors:  James Gierse; Atli Thorarensen; Konstantine Beltey; Erica Bradshaw-Pierce; Luz Cortes-Burgos; Troii Hall; Amy Johnston; Michael Murphy; Olga Nemirovskiy; Shinji Ogawa; Lyle Pegg; Matthew Pelc; Michael Prinsen; Mark Schnute; Jay Wendling; Steve Wene; Robin Weinberg; Arthur Wittwer; Ben Zweifel; Jaime Masferrer
Journal:  J Pharmacol Exp Ther       Date:  2010-04-14       Impact factor: 4.030

3.  Lysophosphatidic acid (LPA) receptors of the EDG family are differentially activated by LPA species. Structure-activity relationship of cloned LPA receptors.

Authors:  K Bandoh; J Aoki; A Taira; M Tsujimoto; H Arai; K Inoue
Journal:  FEBS Lett       Date:  2000-07-28       Impact factor: 4.124

4.  Crystal structure of autotaxin and insight into GPCR activation by lipid mediators.

Authors:  Hiroshi Nishimasu; Shinichi Okudaira; Kotaro Hama; Emiko Mihara; Naoshi Dohmae; Asuka Inoue; Ryuichiro Ishitani; Junichi Takagi; Junken Aoki; Osamu Nureki
Journal:  Nat Struct Mol Biol       Date:  2011-01-16       Impact factor: 15.369

5.  The active site of a zinc-dependent metalloproteinase influences the computed pK(a) of ligands coordinated to the catalytic zinc ion.

Authors:  Jason B Cross; José S Duca; James J Kaminski; Vincent S Madison
Journal:  J Am Chem Soc       Date:  2002-09-18       Impact factor: 15.419

Review 6.  Autotaxin: structure-function and signaling.

Authors:  Anastassis Perrakis; Wouter H Moolenaar
Journal:  J Lipid Res       Date:  2014-02-18       Impact factor: 5.922

7.  Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II.

Authors:  Reva C Lawrence; David T Felson; Charles G Helmick; Lesley M Arnold; Hyon Choi; Richard A Deyo; Sherine Gabriel; Rosemarie Hirsch; Marc C Hochberg; Gene G Hunder; Joanne M Jordan; Jeffrey N Katz; Hilal Maradit Kremers; Frederick Wolfe
Journal:  Arthritis Rheum       Date:  2008-01

Review 8.  Two pathways for lysophosphatidic acid production.

Authors:  Junken Aoki; Asuka Inoue; Shinichi Okudaira
Journal:  Biochim Biophys Acta       Date:  2008-06-24

9.  Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein.

Authors:  M L Stracke; H C Krutzsch; E J Unsworth; A Arestad; V Cioce; E Schiffmann; L A Liotta
Journal:  J Biol Chem       Date:  1992-02-05       Impact factor: 5.157

10.  Synthesis and antifungal activity of 1,2,3-triazole containing fluconazole analogues.

Authors:  Nilkanth G Aher; Vandana S Pore; Nripendra N Mishra; Awanit Kumar; Praveen K Shukla; Aanchal Sharma; Manoj K Bhat
Journal:  Bioorg Med Chem Lett       Date:  2008-12-10       Impact factor: 2.823
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  7 in total

1.  Discovery of BI-2545: A Novel Autotaxin Inhibitor That Significantly Reduces LPA Levels in Vivo.

Authors:  Christian A Kuttruff; Marco Ferrara; Tom Bretschneider; Stefan Hoerer; Sandra Handschuh; Bernd Nosse; Helmut Romig; Paul Nicklin; Gerald J Roth
Journal:  ACS Med Chem Lett       Date:  2017-11-08       Impact factor: 4.345

2.  Molecular modelling guided design, synthesis and QSAR analysis of new small molecule non-lipid autotaxin inhibitors.

Authors:  Souvik Banerjee; Derek D Norman; Shanshan Deng; Sayo O Fakayode; Sue Chin Lee; Abby L Parrill; Wei Li; Duane D Miller; Gabor J Tigyi
Journal:  Bioorg Chem       Date:  2020-08-26       Impact factor: 5.275

Review 3.  Oxidized Lipids in Persistent Pain States.

Authors:  Tabea Osthues; Marco Sisignano
Journal:  Front Pharmacol       Date:  2019-10-15       Impact factor: 5.810

4.  Identifying Novel ATX Inhibitors via Combinatory Virtual Screening Using Crystallography-Derived Pharmacophore Modelling, Docking Study, and QSAR Analysis.

Authors:  Ji-Xia Ren; Rui-Tao Zhang; Hui Zhang
Journal:  Molecules       Date:  2020-03-02       Impact factor: 4.411

5.  Discovery of Potent Selective Nonzinc Binding Autotaxin Inhibitor BIO-32546.

Authors:  Bin Ma; Lei Zhang; Lihong Sun; Zhili Xin; Gnanasambandam Kumaravel; Douglas Marcotte; Jayanth V Chodaparambil; Qin Wang; Angela Wehr; Jing Jing; Victor Sukbong Hong; Ti Wang; Carol Huang; Zhaohui Shao; Sha Mi
Journal:  ACS Med Chem Lett       Date:  2021-06-14       Impact factor: 4.632

6.  Benzoxaboroles-Novel Autotaxin Inhibitors.

Authors:  Kristina Kraljić; Dubravko Jelić; Dinko Žiher; Adam Cvrtila; Snježana Dragojević; Verona Sinković; Milan Mesić
Journal:  Molecules       Date:  2019-09-20       Impact factor: 4.411

Review 7.  The Structural Binding Mode of the Four Autotaxin Inhibitor Types that Differentially Affect Catalytic and Non-Catalytic Functions.

Authors:  Fernando Salgado-Polo; Anastassis Perrakis
Journal:  Cancers (Basel)       Date:  2019-10-16       Impact factor: 6.639
  7 in total

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