Trypsin inhibitors for the treatment of pancreatitis

Trixi Brandl; Oliver Simic; Philip R Skaanderup; Kenji Namoto; Frederic Berst; Claus Ehrhardt; Nikolaus Schiering; Irene Mueller; Julian Woelcke

doi:10.1016/j.bmcl.2016.07.029

Trypsin inhibitors for the treatment of pancreatitis

Bioorg Med Chem Lett. 2016 Sep 1;26(17):4340-4. doi: 10.1016/j.bmcl.2016.07.029. Epub 2016 Jul 17.

Authors

Trixi Brandl¹, Oliver Simic², Philip R Skaanderup², Kenji Namoto², Frederic Berst², Claus Ehrhardt², Nikolaus Schiering², Irene Mueller², Julian Woelcke³

Affiliations

¹ Novartis Pharma AG, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland. Electronic address: [email protected].
² Novartis Pharma AG, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
³ Novartis Pharma AG, Cardio Metabolic Development Franchise, Novartis Campus, CH-4002 Basel, Switzerland.

PMID: 27476144
DOI: 10.1016/j.bmcl.2016.07.029

Abstract

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.

Keywords: Pancreatitis; Trypsin inhibitor; X-ray crystal structure; hERG inhibition.

MeSH terms

Crystallography, X-Ray
Enzyme Activation / drug effects
Humans
Inhibitory Concentration 50
Molecular Structure
Pancreatitis / drug therapy*
Structure-Activity Relationship
Trypsin Inhibitors / chemical synthesis*
Trypsin Inhibitors / chemistry
Trypsin Inhibitors / pharmacology
Trypsin Inhibitors / therapeutic use*

Substances

Trypsin Inhibitors