Pharmacological and pharmacokinetic characterization of 2-piperazine-alpha-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists.
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.
Chen
Chen
C
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA. cchen@neurocrine.com
Tucci
Fabio C
FC
Jiang
Wanlong
W
Tran
Joe A
JA
Fleck
Beth A
BA
Hoare
Sam R
SR
Wen
Jenny
J
Chen
Takung
T
Johns
Michael
M
Markison
Stacy
S
Foster
Alan C
AC
Marinkovic
Dragan
D
Chen
Caroline W
CW
Arellano
Melissa
M
Harman
John
J
Saunders
John
J
Bozigian
Haig
H
Marks
Daniel
D
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
D001596:Benzylamines; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4