Optimization of privileged structures for selective and potent melanocortin subtype-4 receptor ligands

Design, syntheses and structure–activity relationships of piperazine privileged structures containing MC4R agonist compounds 6 were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties. Design, synthe...

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Published in:	Bioorganic & medicinal chemistry letters Vol. 20; no. 15; pp. 4483 - 4486
Main Authors:	Hong, Qingmei, Bakshi, Raman K., Dellureficio, James, He, Shuwen, Ye, Zhixiong, Dobbelaar, Peter H., Sebhat, Iyassu K., Guo, Liangqin, Liu, Jian, Jian, Tianying, Tang, Rui, Kalyani, Rubana N., MacNeil, Tanya, Vongs, Aurawan, Rosenblum, Charles I., Weinberg, David H., Peng, Qingping, Tamvakopoulos, Constantin, Miller, Randy R., Stearns, Ralph A., Cashen, Doreen, Martin, Willian J., Chen, Airu S., Metzger, Joseph M., Chen, Howard Y., Strack, Allison M., Fong, Tung M., Maclntyre, Euan, Van der Ploeg, Lex H.T., Wyvratt, Matthew J., Nargund, Ravi P.
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 01-08-2010 Elsevier
Subjects:	Agonist Animals Biological and medical sciences Humans Ligands MC4R Medical sciences Melanocortin N-acetylated piperazine Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Piperazines - chemical synthesis Piperazines - chemistry Piperazines - pharmacokinetics Privileged structures Rats Rats, Sprague-Dawley Receptor, Melanocortin, Type 4 - agonists Receptor, Melanocortin, Type 4 - metabolism Structure-Activity Relationship Sulfonamide piperazine MC4R Melanocortin Agonist Privileged structures Sulfonamide piperazine N-acetylated piperazine Intravenous administration Rat Nitrogen heterocycle Selectivity Structure activity relation Chemical synthesis Secondary amine Human Sulfonamide Rodentia Benzene derivatives Oral administration In vitro In vivo Vertebrata Mammalia MC4 melanocortin receptor Animal Affinity Carboxamide Fluorine Organic compounds Piperazine derivatives Pharmacokinetics
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Summary:	Design, syntheses and structure–activity relationships of piperazine privileged structures containing MC4R agonist compounds 6 were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties. Design, syntheses and structure–activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.06.038