Small molecule inhibitors of mannan-binding lectin-associated serine Proteases-2 and-3

  • Eur J Med Chem. 2025 May 5:289:117238. doi: 10.1016/j.ejmech.2025.117238.
Mina C Nakhla  1 ,  Janelle Comita  1 ,  Adam B Shapiro  1 ,  Samir H Moussa  1 ,  April Chen  1 ,  Charles J Eyermann  2 ,  John P O'Donnell  1 ,  Alita A Miller  1 ,  Brett A Granger  3
Affiliations
  • 1. Innoviva Specialty Therapeutics, Inc., Waltham, MA, 02451, USA.
  • 2. Boston Drug Design LLC, Lincoln, MA, 01773, USA.
  • 3. Innoviva Specialty Therapeutics, Inc., Waltham, MA, 02451, USA. Electronic address: [email protected].
PMID: 40010268 DOI: 10.1016/j.ejmech.2025.117238
Abstract

The Complement System of innate immunity recognizes, opsonizes, and kills invading pathogens and damaged cells, and stimulates an inflammatory response. Inappropriate or excessive complement activity is associated with a wide variety of pathological conditions, and several drugs targeting complement components have been approved. Here we describe the discovery and structure-activity relationships of a novel class of 2-aminoimidazole-containing inhibitors of mannan-binding lectin-associated serine proteases -2 and -3 (MASP-2 and MASP-3), essential Enzymes for activation of the lectin and alternative pathways of complement, respectively. With a high degree of target selectivity and favorable in vitro pharmacological properties, this inhibitor series has the potential to be developed as treatments for numerous diseases and pathological conditions.

Keywords
Complement; Selectivity; Serine protease; Structure-activity relationship; Structure-based design.
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