Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Aug 2;7(9):857-61.
doi: 10.1021/acsmedchemlett.6b00207. eCollection 2016 Sep 8.

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

Spencer B Jones  1 , Lance A Pfeifer  1 , Thomas J Bleisch  1 , Thomas J Beauchamp  1 , Jim D Durbin  1 , V Joseph Klimkowski  1 , Norman E Hughes  1 , Christopher J Rito  1 , Yen Dao  1 , Joseph M Gruber  1 , Hai Bui  1 , Mark G Chambers  1 , Srinivasan Chandrasekhar  1 , Chaohua Lin  1 , Denis J McCann  1 , Daniel R Mudra  1 , Jennifer L Oskins  1 , Craig A Swearingen  1 , Kannan Thirunavukkarasu  1 , Bryan H Norman  1
Affiliations

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

Spencer B Jones et al. ACS Med Chem Lett. .

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.

Keywords: Autotaxin; LPA; osteoarthritis; tool molecule.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Two biosynthetic routes of lysophosphatidic acid (LPA) production. R groups on lipids = various unsaturated and saturated fatty acid chains.
Figure 2
Figure 2
Cocrystal structure of LPA 22:6 bound to mouse autotaxin.
Figure 3
Figure 3
Cocrystal structure of 1 bound to rat autotaxin. Hydrogen bond distances shown in Å.
Chart 1
Chart 1. Literature Autotaxin Inhibitor PF-8380
Figure 4
Figure 4
Cocrystal structure of PF-8380 bound to rat autotaxin.
Figure 5
Figure 5
Cocrystal structure overlays of 1 and 2 bound to rat autotaxin.
Figure 6
Figure 6
Rationale of pKa dependency on autotaxin inhibitor potency.
Scheme 1
Scheme 1. Synthesis of 9
Reagents and conditions: (a) iPr2EtN, NMP, 80 °C, 75%; (b) 5 N HCl(aq), THF, 50 °C, 80%; (c) 2-chloroacetyl chloride, Et3N, CH2Cl2, 23 °C, 84%; (d) 3-butyn-1-ol, NaH, THF, 0 °C, 23%; (e) CuSO4·5H2O, l-sodium ascorbate, TMSN3, DMF, H2O, 90 °C, 30%.
Figure 7
Figure 7
Rat PK/PD (10 mg/kg) experiment illustrates the correlation between plasma drug concentration and reduction in plasma LPA.
See this image and copyright information in PMC

References

    1. Lawrence R. C.; Felson D. T.; Helmick C. G.; Arnold L. M.; Choi H.; Deyo R. A.; Gabriel S.; Hirsch R.; Hochberg M. C.; Hunder G. G.; Jordan J. M.; Katz J. N.; Kremers H. M.; Wolfe F. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States Part II. Arthritis Rheum. 2008, 58, 26–35. 10.1002/art.23176. - DOI - PMC - PubMed
    1. Gabriel S. E.; Crowson C. S.; Campion M. E.; O’Fallon W. M. Direct medical costs unique to people with arthritis. J. Rheumatol. 1997, 24, 719–25. - PubMed
    1. Laufer S. Osteoarthritis therapy-are there still unmet needs?. Rheumatology 2004, 43, i9–i15. 10.1093/rheumatology/keh103. - DOI - PubMed
    1. Orosa B.; Garcia S.; Conde C. The autotaxin-lysophosphatidic acid pathway in pathogenesis of rheumatoid arthritis. Eur. J. Pharmacol. 2015, 765, 228–233. 10.1016/j.ejphar.2015.08.028. - DOI - PubMed
    1. Bandoh K.; Aoki J.; Taira A.; Tsujimoto M.; Arai H.; Inoue K. Lysophosphatidic acid (LPA) receptors of the EDG family are differentially activated by LPA species. FEBS Lett. 2000, 478, 159–165. 10.1016/S0014-5793(00)01827-5. - DOI - PubMed