Development of ADS051, an oral, gut-restricted, small molecule neutrophil modulator for the treatment of neutrophil-mediated inflammatory diseases

Christopher K. Murphy, Bharat Dixit, Frederick B. Oleson, Roland E. Dolle, Ronald Farquhar, Beth A. McCormick

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Neutrophils are an essential component of the innate immune system; however, uncontrolled neutrophil activity can lead to inflammation and tissue damage in acute and chronic diseases. Despite inclusion of neutrophil presence and activity in clinical evaluations of inflammatory diseases, the neutrophil has been an overlooked therapeutic target. The goal of this program was to design a small molecule regulator of neutrophil trafficking and activity that fulfilled the following criteria: (a) modulates neutrophil epithelial transmigration and activation, (b) lacks systemic exposure, (c) preserves protective host immunity, and (d) is administered orally. The result of this discovery program was ADS051 (also known as BT051), a low permeability, small molecule modulator of neutrophil trafficking and activity via blockade of multidrug resistance protein 2 (MRP2)- and formyl peptide receptor 1 (FPR1)-mediated mechanisms. ADS051, based on a modified scaffold derived from cyclosporine A (CsA), was designed to have reduced affinity for calcineurin with low cell permeability and, thus, a greatly reduced ability to inhibit T-cell function. In cell-based assays, ADS051 did not inhibit cytokine secretion from activated human T cells. Furthermore, in preclinical models, ADS051 showed limited systemic absorption (<1% of total dose) after oral administration, and assessment of ADS051 in human, cell-based systems demonstrated inhibition of neutrophil epithelial transmigration. In addition, preclinical toxicology studies in rats and monkeys receiving daily oral doses of ADS051 for 28 days did not reveal safety risks or ADS051-related toxicity. Our results to date support the clinical development of ADS051 in patients with neutrophil-mediated inflammatory diseases.

Original languageEnglish
Pages (from-to)1434-1446
Number of pages13
JournalFEBS Open Bio
Volume13
Issue number8
DOIs
StatePublished - Aug 2023

Keywords

  • ADS051
  • cyclosporine A
  • formyl peptide receptor 1
  • multidrug resistance protein 2
  • neutrophil transmigration
  • small molecule

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