Design, synthesis, in vitro, and in vivo characterization of phenylpiperazines and pyridinylpiperazines as potent and selective antagonists of the melanocortin-4 receptor.
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.
Tran
Joe A
JA
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130, USA.
Jiang
Wanlong
W
Tucci
Fabio C
FC
Fleck
Beth A
BA
Wen
Jenny
J
Sai
Yang
Y
Madan
Ajay
A
Chen
Ta Kung
TK
Markison
Stacy
S
Foster
Alan C
AC
Hoare
Sam R
SR
Marks
Daniel
D
Harman
John
J
Chen
Caroline W
CW
Arellano
Melissa
M
Marinkovic
Dragan
D
Bozigian
Haig
H
Saunders
John
J
Chen
Chen
C
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
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