Trypsin inhibitors for the treatment of pancreatitis

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 17; pp. 4340 - 4344
• Main Authors: Brandl, Trixi, Simic, Oliver, Skaanderup, Philip R., Namoto, Kenji, Berst, Frederic, Ehrhardt, Claus, Schiering, Nikolaus, Mueller, Irene, Woelcke, Julian
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.09.2016; Elsevier
• Subjects: Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; Enzyme Activation - drug effects; hERG inhibition; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Molecular Structure; Pancreatitis; Pancreatitis - drug therapy; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-Activity Relationship; Trypsin inhibitor; Trypsin Inhibitors - chemical synthesis; Trypsin Inhibitors - chemistry; Trypsin Inhibitors - pharmacology; Trypsin Inhibitors - therapeutic use; X-ray crystal structure; Trypsin inhibitor; AYVQDWAWTUYBGU-RVUATISTSA-N; Pancreatitis; YBZBHUMSHGXQNF-FIBWVYCGSA-N; hERG inhibition; X-ray crystal structure; PZBPHXPZLFDRAP-REWPJTCUSA-N; DIAGNOSIS; HEREDITARY PANCREATITIS; GENE; MUTATIONS; DISCOVERY
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.07.029

[Display omitted] Proline-based trypsin inhibitors occupying the S1–S2–S1′ region were identified by an HTS screening campaign. It was discovered that truncation of the P1′ moiety and appropriate extension into the S4 region led to highly potent trypsin inhibitors with excellent selectivity against related serine proteases and a favorable hERG profile.