Application of cultured human mast cells (CHMC) for the design and structure-activity relationship of IgE-mediated mast cell activation inhibitors

Ankush Argade; Somasekhar Bhamidipati; Hui Li; David Carroll; Jeffrey Clough; Holger Keim; Catherine Sylvain; Alexander B Rossi; Christina Coquilla; Sarkiz D Issakani; Esteban S Masuda; Donald G Payan; Rajinder Singh

doi:10.1016/j.bmcl.2015.03.075

Application of cultured human mast cells (CHMC) for the design and structure-activity relationship of IgE-mediated mast cell activation inhibitors

Bioorg Med Chem Lett. 2015;25(10):2117-21. doi: 10.1016/j.bmcl.2015.03.075. Epub 2015 Mar 31.

Affiliations

¹ Amarit Bioscience, Inc., 428 Oakmead Pkwy, Sunnyvale, CA 94085, USA.
² Rigel, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
³ UCSF, 500 Parnassus Av., San Francisco, CA 94143, USA.
⁴ Amgen, Thousand Oaks, CA 91320, USA.
⁵ Genentech, 1600 Grandview Drive, South San Francisco, CA 94080, USA.
⁶ Rossi Consulting, PO Box 734, Reedsport, OR 97467, USA.
⁷ Rigel, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. Electronic address: rsingh@rigel.com.

PMID: 25872982
DOI: 10.1016/j.bmcl.2015.03.075

Abstract

Here we report the optimization of small molecule inhibitors of human mast cell degranulation via anti-IgE-mediated tryptase release following cross-linking and activation of IgE-loaded FcεR1 receptors. The compounds are selective upstream inhibitors of FcεR1-dependent human mast cell degranulation and proved to be devoid of activity in downstream ionomycin mediated degranulation. Structure-activity relationship (SAR) leading to compound 26 is outlined.

Keywords: Cultured human mast cells (CHMC); Diaminopyrimidine; Immunoglobulin E (IgE); Tryptase.

MeSH terms

Cells, Cultured
Drug Design*
Humans
Immunoglobulin E / immunology*
Mast Cells / cytology
Mast Cells / drug effects*
Mast Cells / immunology
Structure-Activity Relationship

Substances

Immunoglobulin E