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Discovery of a novel small molecule agonist scaffold for the APJ receptor

Content Provider	Scilit
Author	Narayanan, Sanju Maitra, Rangan Deschamps, Jeffery R. Bortoff, Katherine Thomas, James B. Zhang, Yanyan Warner, Keith Vasukuttan, Vineetha Decker, Ann Runyon, Scott P.
Copyright Year	2016
Description	Journal: Bioorganic & Medicinal Chemistry The apelinergic system includes a series of endogenous peptides apelin, ELABELA/TODDLER and their 7-transmembrane G-protein coupled apelin receptor (APJ, AGTRL-1, APLNR). The APJ receptor is an attractive therapeutic target because of its involvement in cardiovascular diseases and potentially other disorders including liver fibrosis, obesity, diabetes, and neuroprotection. To date, pharmacological characterization of the APJ receptor has been limited due to the lack of small molecule functional agonists or antagonists. Through focused screening we identified a drug-like small molecule agonist hit 1 with a functional EC50 value of 21.5±5μM and binding affinity (Ki) of 5.2±0.5μM. Initial structure-activity studies afforded compound 22 having a 27-fold enhancement in potency and the first sub-micromolar full agonist with an EC50 value of 800±0.1nM and Ki of 1.3±0.3μM. Preliminary SAR, synthetic methodology, and in vitro pharmacological characterization indicate this scaffold will serve as a favorable starting point for further refinement of APJ potency and selectivity.
Related Links	http://europepmc.org/articles/pmc4955518?pdf=render https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955518/pdf
Ending Page	3770
Page Count	13
Starting Page	3758
ISSN	09680896
e-ISSN	14643391
DOI	10.1016/j.bmc.2016.06.018
Journal	Bioorganic & Medicinal Chemistry
Issue Number	16
Volume Number	24
Language	English
Publisher	Elsevier BV
Publisher Date	2016-08-01
Access Restriction	Open
Subject Keyword	Journal: Bioorganic & Medicinal Chemistry Medicinal Chemistry Apj Small Molecule Agonist
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Drug Discovery Biochemistry Clinical Biochemistry Molecular Biology Molecular Medicine Pharmaceutical Science

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

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