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Novel tetrahydroquinazolinamines as Selective Histamine 3 Receptor Antagonists for the Treatment of Obesity Ajeet Kumar, Venkata Reddy Pasam, Ravi Kumar Thakur, Maninder Singh, Kartikey Singh, Mahendra Shukla, Anubhav yadav, Shalini Dogra, Chandan Sona, Deepmala Umrao, Swati Jaiswal, Hafsa Ahmad, Mamunur Rashid, Sandeep singh, Muhammad Wahajuddin, Anil Kumar Dwivedi, Mohammad Imran Siddiqi, Jawahar Lal, Rama Pati Tripathi, and Prem N Yadav J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.9b00241 • Publication Date (Web): 18 Apr 2019 Downloaded from http://pubs.acs.org on April 18, 2019
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Journal of Medicinal Chemistry
Novel tetrahydroquinazolinamines as Selective Histamine 3 Receptor Antagonists for the Treatment of Obesity Ajeet Kumar1,†, Venkata Reddy Pasam2,†,Ravi Kumar Thakur2, Maninder Singh3, Kartikey Singh2, Mahendra Shukla4, Anubhav Yadav1, Shalini Dogra1, Chandan Sona1,5, Deepmala Umrao1, Swati Jaiswal4, Hafsa Ahmad4, Mamunur Rashid4, Sandeep K Singh4, Muhammad Wahajuddin4 Anil Kumar Dwivedi4, Mohammad Imran Siddiqi3,5, Jawahar Lal4, Rama Pati Tripathi2,5,6,* and Prem N Yadav1,5*
1Pharmacology 2Medicinal
Division, CSIR-Central Drug Research Institute, Lucknow-226031, India
and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow-
226031, India. 3Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow- 226031, India. 4Pharmaceutics and Pharmacokinetics Division, CSIRCentral Drug Research Institute, Lucknow- 226031, India .5Academy of Scientific and Innovative Research (AcSIR), New Delhi- 110001, India.6Dean, National Institute of Pharmaceutical Education and Research Raebareli, New Transit Campus, Bijnor Road, Sarojani Nagar, Near CRPF Base Camp, Lucknow 226002, U.P., India
†These
authors contributed equally
*Correspondence:
[email protected],
[email protected] Key words: Histamine 3 receptor (H3R), GPCR, obesity, GloSensor, Quinazolinamines
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Abstract The histamine 3 receptor (H3R) is a presynaptic receptor, which modulates several neurotransmitters including histamine and various essential physiological processes, such as feeding, arousal, cognition and pain. The H3R is considered as a drug target for the treatment of several central nervous system disorders. We have synthesized and identified a novel series of 4Aryl-6-methyl-5,6,7,8-tetrahydroquinazolinamines that act as selective H3R antagonist. Among all the synthesized compounds, in vitro and docking studies suggested that 4-methoxy-phenyl substituted tetrahydroquinazolinamine compound 4c has potent and selective H3R antagonist activity (IC50
