title: Design, synthesis, in vitro, and in vivo characterization of phenylpiperazines and pyridinylpiperazines as potent and selective antagonists of the melanocortin-4 receptor.
abstract: Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a K(i) value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130, USA.
authors.forename: Joe A
authors.initials: JA
authors.lastname: Tran
authors.forename: Wanlong
authors.initials: W
authors.lastname: Jiang
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Beth A
authors.initials: BA
authors.lastname: Fleck
authors.forename: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Yang
authors.initials: Y
authors.lastname: Sai
authors.forename: Ajay
authors.initials: A
authors.lastname: Madan
authors.forename: Ta Kung
authors.initials: TK
authors.lastname: Chen
authors.forename: Stacy
authors.initials: S
authors.lastname: Markison
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
authors.forename: Sam R
authors.initials: SR
authors.lastname: Hoare
authors.forename: Daniel
authors.initials: D
authors.lastname: Marks
authors.forename: John
authors.initials: J
authors.lastname: Harman
authors.forename: Caroline W
authors.initials: CW
authors.lastname: Chen
authors.forename: Melissa
authors.initials: M
authors.lastname: Arellano
authors.forename: Dragan
authors.initials: D
authors.lastname: Marinkovic
authors.forename: Haig
authors.initials: H
authors.lastname: Bozigian
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002100:Cachexia / Q000188:drug therapy / Q000209:etiology; D018827:Carcinoma, Lewis Lung / Q000150:complications; D002460:Cell Line; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D004435:Eating / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001596:Benzylamines; C527124:N-(1-(2-(4-(2-methyl-3-(4-chlorophenyl)propionyl)-1-piperazinyl)-5-chlorophenyl)-3-methylbutyl)-3-(dimethylamino)propionamide; D010879:Piperazines; D011725:Pyridines; D044105:Receptor, Melanocortin, Type 4; D000242:Cyclic AMP