Mechanisms of Skin Toxicity Associated with Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators.

Autor:	Shah F; Worldwide Medicinal Chemistry, Pfizer Inc., Cambridge, MA 02139, USA. Electronic address: falgunhshah@gmail.com., Stepan AF; Worldwide Medicinal Chemistry, Pfizer Inc., Cambridge, MA 02139, USA., O'Mahony A; Bioseek Inc., Division of DiscoverX, 310 Utah Avenue, South San Francisco, CA 94080, USA., Velichko S; Bioseek Inc., Division of DiscoverX, 310 Utah Avenue, South San Francisco, CA 94080, USA., Folias AE; Bioseek Inc., Division of DiscoverX, 310 Utah Avenue, South San Francisco, CA 94080, USA., Houle C; Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340, USA., Shaffer CL; Neuroscience and Pain Research Unit, Pfizer Inc., Cambridge, MA 02139, USA., Marcek J; Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340, USA., Whritenour J; Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340, USA., Stanton R; Worldwide Medicinal Chemistry, Pfizer Inc., Cambridge, MA 02139, USA., Berg EL; Bioseek Inc., Division of DiscoverX, 310 Utah Avenue, South San Francisco, CA 94080, USA. Electronic address: eberg@discoverx.com.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2017 Jul 20; Vol. 24 (7), pp. 858-869.e5. Date of Electronic Publication: 2017 Jun 29.
DOI:	10.1016/j.chembiol.2017.06.003
Abstrakt:	Cutaneous reactions represent one of the most common adverse drug effects observed in clinical trials leading to substantial compound attrition. Three negative allosteric modulators (NAMs) of metabotropic glutamate receptors (mGluRs), which represent an important target for neurological diseases, developed by Pfizer, were recently failed in preclinical development due to delayed type IV skin hypersensitivity observed in non-human primates (NHPs). Here we employed large-scale phenotypic profiling in standardized panels of human primary cell/co-culture systems to characterize the skin toxicity mechanism(s) of mGluR5 NAMs from two different series. Investigation of a database of chemicals tested in these systems and transcriptional profiling suggested that the mechanism of toxicity may involve modulation of nuclear receptor targets RAR/RXR, and/or VDR with AhR antagonism. The studies reported here demonstrate how phenotypic profiling of preclinical drug candidates using human primary cells can provide insights into the mechanisms of toxicity and inform early drug discovery and development campaigns. (Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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