Structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents
Antagonism of alphav beta6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an alphav beta3 antagonist lead and through simple variation in the nature and position of aryl substituent, the discovery of compounds with improved alp...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
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American Chemical Society
2014
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| Online Access: | https://eprints.nottingham.ac.uk/29558/ |
| _version_ | 1848793810490884096 |
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| author | Adams, James Anderson, Edward C. Blackham, Emma E. Chiu, Yin Wa Ryan Clarke, Thomas Eccles, Natasha Gill, Luke A. Haye, Joshua J. Haywood, Harvey T. Hoenig, Christian R. Russell, Hannah L. Smedley, Christopher Tipping, William J. Tongue, Tom Wood, Charlotte C. Yeung, Jason Rowedder, James E. Fray, Michael J. Mcinally, Thomas Macdonald, Simon J.F. |
| author_facet | Adams, James Anderson, Edward C. Blackham, Emma E. Chiu, Yin Wa Ryan Clarke, Thomas Eccles, Natasha Gill, Luke A. Haye, Joshua J. Haywood, Harvey T. Hoenig, Christian R. Russell, Hannah L. Smedley, Christopher Tipping, William J. Tongue, Tom Wood, Charlotte C. Yeung, Jason Rowedder, James E. Fray, Michael J. Mcinally, Thomas Macdonald, Simon J.F. |
| author_sort | Adams, James |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Antagonism of alphav beta6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an alphav beta3 antagonist lead and through simple variation in the nature and position of aryl substituent, the discovery of compounds with improved alphav beta6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery programme. Compounds 33S and 43E1 are pan alphav antagonists having ca 100 nM potency against alphav beta3, alphav beta5, alphav beta6 and alphav beta8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for alphav beta3 and alphav beta5. |
| first_indexed | 2025-11-14T19:06:13Z |
| format | Article |
| id | nottingham-29558 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:06:13Z |
| publishDate | 2014 |
| publisher | American Chemical Society |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-295582020-05-04T16:53:43Z https://eprints.nottingham.ac.uk/29558/ Structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents Adams, James Anderson, Edward C. Blackham, Emma E. Chiu, Yin Wa Ryan Clarke, Thomas Eccles, Natasha Gill, Luke A. Haye, Joshua J. Haywood, Harvey T. Hoenig, Christian R. Russell, Hannah L. Smedley, Christopher Tipping, William J. Tongue, Tom Wood, Charlotte C. Yeung, Jason Rowedder, James E. Fray, Michael J. Mcinally, Thomas Macdonald, Simon J.F. Antagonism of alphav beta6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an alphav beta3 antagonist lead and through simple variation in the nature and position of aryl substituent, the discovery of compounds with improved alphav beta6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery programme. Compounds 33S and 43E1 are pan alphav antagonists having ca 100 nM potency against alphav beta3, alphav beta5, alphav beta6 and alphav beta8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for alphav beta3 and alphav beta5. American Chemical Society 2014-09-19 Article PeerReviewed Adams, James, Anderson, Edward C., Blackham, Emma E., Chiu, Yin Wa Ryan, Clarke, Thomas, Eccles, Natasha, Gill, Luke A., Haye, Joshua J., Haywood, Harvey T., Hoenig, Christian R., Russell, Hannah L., Smedley, Christopher, Tipping, William J., Tongue, Tom, Wood, Charlotte C., Yeung, Jason, Rowedder, James E., Fray, Michael J., Mcinally, Thomas and Macdonald, Simon J.F. (2014) Structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents. ACS Medicinal Chemistry Letters, 5 (11). pp. 1207-1212. ISSN 1948-5875 integrins antagonist pulmonary fibrosis αvβ6 αvβ3 β-amino acids http://pubs.acs.org/doi/abs/10.1021/ml5002079 doi:10.1021/ml5002079 doi:10.1021/ml5002079 |
| spellingShingle | integrins antagonist pulmonary fibrosis αvβ6 αvβ3 β-amino acids Adams, James Anderson, Edward C. Blackham, Emma E. Chiu, Yin Wa Ryan Clarke, Thomas Eccles, Natasha Gill, Luke A. Haye, Joshua J. Haywood, Harvey T. Hoenig, Christian R. Russell, Hannah L. Smedley, Christopher Tipping, William J. Tongue, Tom Wood, Charlotte C. Yeung, Jason Rowedder, James E. Fray, Michael J. Mcinally, Thomas Macdonald, Simon J.F. Structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents |
| title | Structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents |
| title_full | Structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents |
| title_fullStr | Structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents |
| title_full_unstemmed | Structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents |
| title_short | Structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents |
| title_sort | structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents |
| topic | integrins antagonist pulmonary fibrosis αvβ6 αvβ3 β-amino acids |
| url | https://eprints.nottingham.ac.uk/29558/ https://eprints.nottingham.ac.uk/29558/ https://eprints.nottingham.ac.uk/29558/ |