title: Pharmacological and pharmacokinetic characterization of 2-piperazine-alpha-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists.
abstract: A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8-12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA. cchen@neurocrine.com
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Wanlong
authors.initials: W
authors.lastname: Jiang
authors.forename: Joe A
authors.initials: JA
authors.lastname: Tran
authors.forename: Beth A
authors.initials: BA
authors.lastname: Fleck
authors.forename: Sam R
authors.initials: SR
authors.lastname: Hoare
authors.forename: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Takung
authors.initials: T
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Johns
authors.forename: Stacy
authors.initials: S
authors.lastname: Markison
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
authors.forename: Dragan
authors.initials: D
authors.lastname: Marinkovic
authors.forename: Caroline W
authors.initials: CW
authors.lastname: Chen
authors.forename: Melissa
authors.initials: M
authors.lastname: Arellano
authors.forename: John
authors.initials: J
authors.lastname: Harman
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Haig
authors.initials: H
authors.lastname: Bozigian
authors.forename: Daniel
authors.initials: D
authors.lastname: Marks
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002100:Cachexia / Q000188:drug therapy*; D018938:Caco-2 Cells; D018827:Carcinoma, Lewis Lung; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008968:Molecular Conformation; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D001596:Benzylamines; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4