title: Design, synthesis of diaminopyrimidine inhibitors targeting IgE- and IgG-mediated activation of Fc receptor signaling.
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.
authors.affiliation: Amarit Bioscience, Inc., 428 Oakmead Pkwy, Sunnyvale, CA 94085, USA.
authors.forename: Ankush
authors.initials: A
authors.lastname: Argade
authors.affiliation: Rigel, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Somasekhar
authors.initials: S
authors.lastname: Bhamidipati
authors.affiliation: Rigel, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Genentech, 1600 Grandview Drive, South San Francisco, CA 94080, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Sylvain
authors.affiliation: Rigel, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Clough
authors.affiliation: UCSF, 500 Parnassus Av., San Francisco, CA 94143, USA.
authors.forename: David
authors.initials: D
authors.lastname: Carroll
authors.affiliation: Amgen, Thousand Oaks, CA 91320, USA.
authors.forename: Holger
authors.initials: H
authors.lastname: Keim
authors.affiliation: Rigel, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Braselmann
authors.affiliation: Rigel, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Taylor
authors.affiliation: 330 Port Royal Avenue, Foster City, CA 94404, USA.
authors.forename: Haoran
authors.initials: H
authors.lastname: Zhao
authors.affiliation: 30 Walmer Close, Southwater, Sussex RH13 9XY, UK.
authors.forename: Ellen
authors.initials: E
authors.lastname: Herlaar
authors.affiliation: Rigel, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Sarkiz D
authors.initials: SD
authors.lastname: Issakani
authors.affiliation: Five Prime Therapeutics, Inc., 2 Corporate Dr., South San Francisco, CA 94080, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Wong
authors.affiliation: Rigel, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Esteban S
authors.initials: ES
authors.lastname: Masuda
authors.affiliation: Rigel, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Payan
authors.affiliation: Rigel, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. Electronic address: rsingh@rigel.com.
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
mesh_terms: D015195:Drug Design; D007073:Immunoglobulin E / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D011743:Pyrimidines / Q000494:pharmacology*; D011961:Receptors, Fc / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007074:Immunoglobulin G; D011743:Pyrimidines; D011961:Receptors, Fc; D007073:Immunoglobulin E
keywords: Cultured human mast cells (CHMC); Diaminopyrimidine; Immunoglobulin-E and -G (IgE and IgG); Receptor for Fc portion of immunoglobulins (FcR); Syk kinase