Identification of novel β-lactams and pyrrolidinone derivatives as selective Histamine-3 receptor (H3R) modulators as possible anti-obesity agents.

Autor: Ghoshal A; Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, 226031, India., Kumar A; Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India., Yugandhar D; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India; Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India., Sona C; Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India., Kuriakose S; Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India., Nagesh K; Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India., Rashid M; Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India., Singh SK; Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India., Wahajuddin M; Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India., Yadav PN; Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India. Electronic address: pn.yadav@cdri.res.in., Srivastava AK; Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India; Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India. Electronic address: ajayk.srivastava@cdri.res.in.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2018 May 25; Vol. 152, pp. 148-159. Date of Electronic Publication: 2018 Apr 26.
DOI: 10.1016/j.ejmech.2018.04.020
Abstrakt: Four series of structurally related β-lactams, 2,5-pyrrolidinediones, azaspirodecatrienediones (ASDT) and dihydropyrroloquinoxalinetriones (DPQT) were synthesized by utilizing post-Ugi modifications in one-pot, and their activity towards human histamine-3 receptor (H3R) was evaluated. Out of 94 compounds, screened against histamine-3 receptor (H3R), 21 compounds showed high H3R selective agonist property with EC 50 values ranging from 187 nM to 0.1 nM, whereas none of the compound was found to have the affinity towards other receptors of histamine family such as histamine H1, H2, and H4 receptor. All active compounds have no assay interference activity as determined by in-silico analysis and receptor independent luciferase assay and cell cytotoxicity assay. Given the important role of H3R in hypophagia, we also evaluated the in vivo effect of the representative compound 6k on the cumulative food intake in diet induce obese C57BL6/J mice. Interestingly, we observed that single dose administration (20 mg/kg, intraperitoneal injection) of 6k significantly suppressed cumulative food intake, while no significant effect was observed at 10 mg/kg. These results suggest that β-lactams, 2,5-pyrrolidinediones, azaspirodecatrienediones (ASDT) and dihydropyrroloquinoxalinetriones (DPQT) could be useful for the development of anti-obesity candidate drugs.
(Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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