OpenLB
Open Library of Bioscience
Advanced Search
Journal of medicinal chemistry
02 22, 2024;67 (4): 2907-2940.

BAY-9835: Discovery of the First Orally Bioavailable ADAMTS7 Inhibitor.

Daniel Meibom, Pierre Wasnaire, Kristin Beyer, Andreas Broehl, Yolanda Cancho-Grande, Nadine Elowe, Kerstin Henninger, Sarah Johannes, Natalia Jungmann, Tanja Krainz, Niels Lindner, Stefanie Maassen, Bryan MacDonald, Denis Menshykau, Joachim Mittendorf, Guzman Sanchez, Martina Schaefer, Eric Stefan, Afra Torge, Yi Xing, Dmitry Zubov
Author Information
  1. Daniel Meibom: Bayer AG, 42113 Wuppertal, Germany. ORCID
  2. Pierre Wasnaire: Bayer AG, 42113 Wuppertal, Germany.
  3. Kristin Beyer: Bayer AG, 42113 Wuppertal, Germany.
  4. Andreas Broehl: Bayer AG, 42113 Wuppertal, Germany.
  5. Yolanda Cancho-Grande: Bayer AG, 42113 Wuppertal, Germany.
  6. Nadine Elowe: Broad Institute, 02142 Cambridge, United States.
  7. Kerstin Henninger: Bayer AG, 42113 Wuppertal, Germany.
  8. Sarah Johannes: Bayer AG, 42113 Wuppertal, Germany.
  9. Natalia Jungmann: Bayer AG, 42113 Wuppertal, Germany.
  10. Tanja Krainz: Broad Institute, 02142 Cambridge, United States.
  11. Niels Lindner: Bayer AG, 42113 Wuppertal, Germany.
  12. Stefanie Maassen: Bayer AG, 42113 Wuppertal, Germany.
  13. Bryan MacDonald: Broad Institute, 02142 Cambridge, United States. ORCID
  14. Denis Menshykau: Bayer AG, 42113 Wuppertal, Germany.
  15. Joachim Mittendorf: Bayer AG, 42113 Wuppertal, Germany.
  16. Guzman Sanchez: Villapharma Research, 30320 Murcia, Spain.
  17. Martina Schaefer: Bayer AG, 13353 Berlin, Germany.
  18. Eric Stefan: Broad Institute, 02142 Cambridge, United States.
  19. Afra Torge: Bayer AG, 42113 Wuppertal, Germany.
  20. Yi Xing: Broad Institute, 02142 Cambridge, United States.
  21. Dmitry Zubov: Bayer AG, 42113 Wuppertal, Germany.
PMID: 38348661 DOI: 10.1021/acs.jmedchem.3c02036

Abstract

The matrix metalloprotease ADAMTS7 has been identified by multiple genome-wide association studies as being involved in the development of coronary artery disease. Subsequent research revealed the proteolytic function of the enzyme to be relevant for atherogenesis and restenosis after vessel injury. Based on a publicly known dual ADAMTS4/ADAMTS5 inhibitor, we have in silico designed an ADAMTS7 inhibitor of the catalytic domain, which served as a starting point for an optimization campaign. Initially our inhibitors suffered from low selectivity vs MMP12. An X-ray cocrystal structure inspired us to exploit amino acid differences in the binding site of MMP12 and ADAMTS7 to improve selectivity. Further optimization composed of employing 5-membered heteroaromatic groups as hydantoin substituents to become more potent on ADAMTS7. Finally, fine-tuning of DMPK properties yielded BAY-9835, the first orally bioavailable ADAMTS7 inhibitor. Further optimization to improve selectivity vs ADAMTS12 seems possible, and a respective starting point could be identified.

References

  1. J Cell Mol Med. 2019 Jun;23(6):3974-3983 [PMID: 30903650]
  2. Nat Rev Genet. 2017 Jun;18(6):331-344 [PMID: 28286336]
  3. Am J Hum Genet. 2013 Mar 7;92(3):366-74 [PMID: 23415669]
  4. J Biol Chem. 2012 Nov 16;287(47):39554-63 [PMID: 23019333]
  5. JACC Basic Transl Sci. 2021 Jul 26;6(7):610-623 [PMID: 34368511]
  6. Int J Mol Med. 2020 Feb;45(2):532-542 [PMID: 31894258]
  7. J Cell Sci. 2007 Oct 15;120(Pt 20):3544-52 [PMID: 17895370]
  8. Methods Mol Med. 2007;139:1-30 [PMID: 18287662]
  9. Circulation. 2015 Mar 31;131(13):1191-201 [PMID: 25712208]
  10. Physiol Genomics. 2016 Nov 1;48(11):810-815 [PMID: 27614204]
  11. J Med Chem. 2016 Jun 23;59(12):5810-22 [PMID: 27194201]
  12. Sci China Life Sci. 2015 Jul;58(7):674-81 [PMID: 25921940]
  13. Basic Res Cardiol. 2020 Nov 30;115(6):73 [PMID: 33258000]
  14. Matrix Biol. 2018 Oct;71-72:225-239 [PMID: 29885460]
  15. Circ Res. 2023 Sep 29;133(8):674-686 [PMID: 37675562]
  16. J Cell Sci. 2009 Aug 15;122(Pt 16):2906-13 [PMID: 19638407]
  17. Circulation. 2015 Mar 31;131(13):1202-1213 [PMID: 25712206]
  18. Curr Atheroscler Rep. 2023 Aug;25(8):447-455 [PMID: 37354304]
  19. Lancet. 2011 Jan 29;377(9763):383-92 [PMID: 21239051]
  20. Adv Biochem. 2013;1(3): [PMID: 24222922]
  21. J Med Chem. 2017 Jul 13;60(13):5933-5939 [PMID: 28613895]
  22. Gynecol Oncol. 2019 Sep;154(3):495-504 [PMID: 31204077]
  23. Front Mol Biosci. 2021 Apr 30;8:686763 [PMID: 33996918]
  24. J Enzyme Inhib Med Chem. 2021 Dec;36(1):2160-2169 [PMID: 34587841]
  25. Genome Biol. 2015 May 30;16:113 [PMID: 26025392]
  26. Cells Tissues Organs. 2023;212(4):285-292 [PMID: 35462367]
  27. Sci Rep. 2017 Jun 16;7(1):3753 [PMID: 28623250]
  28. J Med Chem. 2014 Dec 26;57(24):10476-85 [PMID: 25415648]
  29. Dig Dis Sci. 2011 Nov;56(11):3281-7 [PMID: 21559743]
  30. JCI Insight. 2018 Apr 5;3(7): [PMID: 29618652]
  31. Circ Res. 2021 Aug 6;129(4):471-473 [PMID: 34351799]
  32. Nat Commun. 2020 Jul 30;11(1):3808 [PMID: 32732999]
  33. Circulation. 2015 Mar 31;131(13):1156-9 [PMID: 25712207]
  34. Nat Genet. 2011 Mar 06;43(4):333-8 [PMID: 21378990]
  35. Biochem Biophys Res Commun. 2016 Mar 11;471(3):380-5 [PMID: 26872430]
  36. J Am Heart Assoc. 2017 Oct 31;6(11): [PMID: 29089340]
  37. PLoS One. 2011 Apr 11;6(4):e18473 [PMID: 21494557]
  38. Circulation. 2023 Feb 28;147(9):743-745 [PMID: 36848412]
  39. Mol Cell Proteomics. 2022 Apr;21(4):100223 [PMID: 35283288]
  40. Clin Sci (Lond). 2016 Feb;130(3):127-50 [PMID: 26678170]
  41. J Oncol. 2020 Aug 20;2020:9431560 [PMID: 32884571]
  42. J Med Chem. 2022 Dec 8;65(23):15513-15539 [PMID: 36446632]
  43. Circ Res. 2009 Mar 13;104(5):688-98 [PMID: 19168437]
  44. FASEB J. 2006 May;20(7):988-90 [PMID: 16585064]
  45. Ann Transl Med. 2020 Mar;8(6):301 [PMID: 32355745]
  46. Mol Cell Biol. 2009 Aug;29(15):4201-19 [PMID: 19487464]
  47. Nat Rev Dis Primers. 2019 Aug 16;5(1):56 [PMID: 31420554]
  48. J Cell Biochem. 2020 Jan;121(1):468-481 [PMID: 31236983]
  49. Circulation. 2023 Feb 28;147(9):728-742 [PMID: 36562301]
  50. Oncogene. 2010 May 20;29(20):3025-32 [PMID: 20208563]
  51. Circ Res. 2021 Aug 6;129(4):458-470 [PMID: 34176299]
  52. Arterioscler Thromb Vasc Biol. 2019 Apr;39(4):538-545 [PMID: 30816799]
  53. J Med Chem. 2021 Mar 25;64(6):2937-2952 [PMID: 33719441]
  54. Atherosclerosis. 2020 Mar;296:11-17 [PMID: 32005000]
  55. Genes (Basel). 2023 Feb 16;14(2): [PMID: 36833435]
  56. Am J Physiol Cell Physiol. 2022 Sep 1;323(3):C651-C665 [PMID: 35785985]
  57. Am J Pathol. 2016 Sep;186(9):2449-61 [PMID: 27449198]
  58. Ann Oncol. 2017 Mar 1;28(3):604-610 [PMID: 27993815]

MeSH Term

Humans
ADAMTS7 Protein
Genome-Wide Association Study
Matrix Metalloproteinase 12
Atherosclerosis
Coronary Artery Disease

Chemicals

ADAMTS7 Protein
Matrix Metalloproteinase 12
ADAMTS7 protein, human
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 1

Word Cloud

Created with Highcharts 10.0.0ADAMTS7inhibitoroptimizationselectivityidentifiedstartingpointvsMMP12improvematrixmetalloproteasemultiplegenome-wideassociationstudiesinvolveddevelopmentcoronaryarterydiseaseSubsequentresearchrevealedproteolyticfunctionenzymerelevantatherogenesisrestenosisvesselinjuryBasedpubliclyknowndualADAMTS4/ADAMTS5silicodesignedcatalyticdomainservedcampaignInitiallyinhibitorssufferedlowX-raycocrystalstructureinspiredusexploitaminoaciddifferencesbindingsitecomposedemploying5-memberedheteroaromaticgroupshydantoinsubstituentsbecomepotentFinallyfine-tuningDMPKpropertiesyieldedBAY-9835firstorallybioavailableADAMTS12seemspossiblerespectiveBAY-9835:DiscoveryFirstOrallyBioavailableInhibitor

Similar Articles

Cited By