Michael Berlin

ADVERTISEMENT RETURN TO ISSUEPREVPerspectiveNEXTHistamine H3 Receptor as a Drug Discovery TargetMichael Berlin*, Christopher W. Boyce, and Manuel de Lera RuizView Author Information Chemical Research, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States *To whom correspondence should be addressed. Phone: 1-908-740-3909. Fax: 1-908-740-7152. E-mail: [email protected]Cite this: J. Med. Chem. 2011, 54, 1, 26–53Publication Date (Web):November 9, 2010Publication History Received15 January 2010Published online9 November 2010Published inissue 13 January 2011https://pubs.acs.org/doi/10.1021/jm100064dhttps://doi.org/10.1021/jm100064dreview-articleACS PublicationsCopyright © 2010 American Chemical SocietyRequest reuse permissionsArticle Views6147Altmetric-Citations124LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Agonists,Amines,Antagonists,Receptors,Rodent models Get e-Alerts

The mammalian SWItch/Sucrose Non-Fermentable (SWI/SNF) helicase SMARCA4 is frequently mutated in cancer and inactivation results in a cellular dependence on its paralog, SMARCA2, thus making SMARCA2 an attractive synthetic lethal target. However, published data indicates that achieving a high degree of selective SMARCA2 inhibition is likely essential to afford an acceptable therapeutic index, and realizing this objective is challenging due to the homology with the SMARCA4 paralog. Herein we report the discovery of a potent and selective SMARCA2 proteolysis-targeting chimera molecule (PROTAC), A947. Selective SMARCA2 degradation is achieved in the absence of selective SMARCA2/4 PROTAC binding and translates to potent in vitro growth inhibition and in vivo efficacy in SMARCA4 mutant models, compared to wild type models. Global ubiquitin mapping and proteome profiling reveal no unexpected off-target degradation related to A947 treatment. Our study thus highlights the ability to transform a non-selective SMARCA2/4-binding ligand into a selective and efficacious in vivo SMARCA2-targeting PROTAC, and thereby provides a potential new therapeutic opportunity for patients whose tumors contain SMARCA4 mutations.

This chapter focuses on the expression of the 28 transient receptor potential canonicals (TRP) that are found in mammals. It summarizes the current knowledge regarding the expression and functional role of TRP channels for Ca2+ homeostasis in cardiomyocytes and cardiac fibroblasts, their contribution to cardiac contractility and conduction, by knockdown/knockout of the corresponding genes, or by the use of specific channel inhibitors. It also summarizes the large body of reports assigning TRP-channel expression in two cardiac cell types—cardiomyocytes and cardiac fibroblasts. However, the channels and pumps mediating the fast Ca2+ cycling during beat-to-beat cardiac action are not only relevant for physiological cardiac functions but also for pathological processes such as development of pathological cardiac remodeling and development of heart failure. Based on the influence of Ca2+ signaling on cardiomyocyte physiology, a role of transient receptor potential canonical channels was proposed in signaling cascades mediating the development of cardiac hypertrophy and remodeling.

The histamine H(3) receptor is involved in the central and peripheral regulation of levels of histamine and other neurotransmitters (e.g., acetylcholine, noradrenaline, dopamine, serotonin and GABA), which sets it up as a target in the treatment of various CNS (e.g., depression, schizophrenia, ADHD, dementia, neuropathic pain and sleep disorders), metabolic syndrome (e.g., obesity) and allergic disorders. Novel chemical series from the most recent 2 years of patent literature have been reviewed. While overall structural diversity is moderate, these represent or relate to some of the compounds progressing through clinical trials (e.g., GSK-189254). However, an H(3) receptor drug still has yet to reach the market. Patenting activity is likely to remain high in the near future, bolstered by the commercial promise of potential H(3) receptor drugs.

A synthesis of (+)-desmethoxymitomycin A is described. The critical step is a highly stereoselective cyclization of an aziridinyl radical to afford a tetracycle having the same relative and absolute stereochemistry as mitomycin A and C.