1owj Citations

Identification of novel binding interactions in the development of potent, selective 2-naphthamidine inhibitors of urokinase. Synthesis, structural analysis, and SAR of N-phenyl amide 6-substitution.

J Med Chem 47 303-24 (2004)
Related entries: 1owd, 1owe, 1owh, 1owi, 1owk

Cited: 34 times
EuropePMC logo PMID: 14711304

Abstract

The preparation and assessment of biological activity of 6-substituted 2-naphthamidine inhibitors of the serine protease urokinase plasminogen activator (uPA, or urokinase) is described. 2-Naphthamidine was chosen as a starting point based on synthetic considerations and on modeling of substituent vectors. Phenyl amides at the 6-position were found to improve binding; replacement of the amide with other two-atom linkers proved ineffective. The phenyl group itself is situated near the S1' subsite; substitutions off of the phenyl group accessed S1' and other distant binding regions. Three new points of interaction were defined and explored through ring substitution. A solvent-exposed salt bridge with the Asp60A carboxylate was formed using a 4-alkylamino group, improving affinity to K(i) = 40 nM. Inhibitors also accessed two hydrophobic regions. One interaction is characterized by a tight hydrophobic fit made with a small dimple largely defined by His57 and His99; a weaker, less specific interaction involves alkyl groups reaching into the broad prime-side protein binding region near Val41 and the Cys42-Cys58 disulfide, displacing water molecules and leading to small gains in activity. Many inhibitors accessed two of these three regions. Affinities range as low as K(i) = 6 nM, and many compounds had K(i) < 100 nM, while moderate to excellent selectivity was gained versus four of five members of a panel of relevant serine proteases. Also, some selectivity against trypsin was generated via the interaction with Asp60A. X-ray structures of many of these compounds were used to inform our inhibitor design and to increase our understanding of key interactions. In combination with our exploration of 8-substitution patterns, we have identified a number of novel binding interactions for uPA inhibitors.

Reviews citing this publication (6)

  1. Fragment-based lead discovery. Rees DC, Congreve M, Murray CW, Carr R. Nat Rev Drug Discov 3 660-672 (2004)
  2. Fragment-based drug discovery: opportunities for organic synthesis. St Denis JD, Hall RJ, Murray CW, Heightman TD, Rees DC. RSC Med Chem 12 321-329 (2020)
  3. Plasminogen activation system in oral cancer: Relevance in prognosis and therapy (Review). Wyganowska-Świątkowska M, Jankun J. Int J Oncol 47 16-24 (2015)
  4. Total syntheses of polyketide-derived bioactive natural products. Tatsuta K, Hosokawa S. Chem Rec 6 217-233 (2006)
  5. Investigation of the structural requirements for N-methyl-D-aspartate receptor positive and negative allosteric modulators based on 2-naphthoic acid. Irvine MW, Fang G, Sapkota K, Burnell ES, Volianskis A, Costa BM, Culley G, Collingridge GL, Monaghan DT, Jane DE. Eur J Med Chem 164 471-498 (2019)
  6. Urokinase plasminogen activator as an anti-metastasis target: inhibitor design principles, recent amiloride derivatives, and issues with human/mouse species selectivity. El Salamouni NS, Buckley BJ, Ranson M, Kelso MJ, Yu H. Biophys Rev 14 277-301 (2022)

Articles citing this publication (28)