Design, synthesis of diaminopyrimidine inhibitors targeting IgE- and IgG-mediated activation of Fc receptor signaling

Ankush Argade; Somasekhar Bhamidipati; Hui Li; Catherine Sylvain; Jeffrey Clough; David Carroll; Holger Keim; Sylvia Braselmann; Vanessa Taylor; Haoran Zhao; Ellen Herlaar; Sarkiz D Issakani; Brian R Wong; Esteban S Masuda; Donald G Payan; Rajinder Singh

doi:10.1016/j.bmcl.2015.03.072

Design, synthesis of diaminopyrimidine inhibitors targeting IgE- and IgG-mediated activation of Fc receptor signaling

Bioorg Med Chem Lett. 2015;25(10):2122-8. doi: 10.1016/j.bmcl.2015.03.072. Epub 2015 Apr 1.

Authors

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 Genentech, 1600 Grandview Drive, South San Francisco, CA 94080, USA.
⁴ UCSF, 500 Parnassus Av., San Francisco, CA 94143, USA.
⁵ Amgen, Thousand Oaks, CA 91320, USA.
⁶ 330 Port Royal Avenue, Foster City, CA 94404, USA.
⁷ 30 Walmer Close, Southwater, Sussex RH13 9XY, UK.
⁸ Five Prime Therapeutics, Inc., 2 Corporate Dr., South San Francisco, CA 94080, USA.
⁹ Rigel, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. Electronic address: [email protected].

PMID: 25891105
DOI: 10.1016/j.bmcl.2015.03.072

Abstract

Using cultured human mast cells (CHMC) the optimization of 2,4-diaminopyrimidine compounds leading to 22, R406 is described. Compound 22 is a potent upstream inhibitor of mast cell degranulation and its mechanism of action is via inhibition of Syk kinase. Compound 22 has significant activity in inhibiting both IgE- and IgG-mediated activation of Fc receptor (FcR) in mast cells and basophils, and in addition inhibits Syk kinase-dependent activity of FcR-mediated activation of monocytes, macrophages, neutrophils, and B cell receptor (BCR)-mediated activation of B lymphocytes. Overall, the biological activity of 22 suggests that it has potential for application as a novel therapeutic for the treatment of an array of autoimmune maladies and hematological malignancies.

Keywords: Cultured human mast cells (CHMC); Diaminopyrimidine; Immunoglobulin-E and -G (IgE and IgG); Receptor for Fc portion of immunoglobulins (FcR); Syk kinase.

MeSH terms

Drug Design*
Immunoglobulin E / immunology*
Immunoglobulin G / immunology*
Pyrimidines / pharmacology*
Receptors, Fc / metabolism*
Signal Transduction / drug effects*

Substances

Immunoglobulin G
Pyrimidines
Receptors, Fc
Immunoglobulin E