W Mike Flanagan

Publications (2)5.3 Total impact

• Article: Structure-activity relationship (SAR) of the α-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists.

  Min Zhong, Emily J Hanan, Wang Shen, Minna Bui, Michelle R Arkin, Kenneth J Barr, Marc J Evanchik, Ute Hoch, Jennifer Hyde, Jose R Martell, Johan D Oslob, Kumar Paulvannan, Saileta Prabhu, Jeffrey A Silverman, Jasmin Wright, Chul H Yu, Jiang Zhu, W Mike Flanagan
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  ABSTRACT: This letter describes the structure-activity relationship (SAR) of the 'right-wing' α-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists. Novel (S)-substituted heteroaryl-bearing α-amino acids have been identified as replacements of the 'right-wing' (S)-2,3-diaminopropanoic acid (DAP) moiety. Improvement of potency in the Hut-78 assay in the presence of 10% human serum has also been achieved.
  Bioorganic & medicinal chemistry letters 01/2011; 21(1):307-10. · 2.65 Impact Factor
• Article: Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists.

  Min Zhong, Wang Shen, Kenneth J Barr, Jennifer P Arbitrario, Michelle R Arkin, Minna Bui, Teresa Chen, Brian C Cunningham, Marc J Evanchik, Emily J Hanan, [......], Chris E Lawrence, Jose R Martell, Johan D Oslob, Kumar Paulvannan, Saileta Prabhu, Jeffrey A Silverman, Jasmin Wright, Chul H Yu, Jiang Zhu, W Mike Flanagan
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  ABSTRACT: This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model.
  Bioorganic & medicinal chemistry letters 09/2010; 20(17):5269-73. · 2.65 Impact Factor