Pyrrolidinones as orally bioavailable antagonists of the human melanocortin-4 receptor with anti-cachectic activity.
A series of pyrrolidinones derived from phenylalanines were synthesized as potent antagonists of the human melanocortin-4 receptor. These compounds showed high potencies and selectivities, and several of them had good oral bioavailabilities. In addition, 12e demonstrated in vivo efficacy in a murine cachexia model.
Tran
Joe A
JA
Department of Medicinal Chemistry, Neurocrine Biosciences Inc, San Diego, CA 92130, USA.
Tucci
Fabio C
FC
Jiang
Wanlong
W
Marinkovic
Dragan
D
Chen
Caroline W
CW
Arellano
Melissa
M
Markison
Stacy
S
Fleck
Beth A
BA
Wen
Jenny
J
White
Nicole S
NS
Pontillo
Joseph
J
Saunders
John
J
Marks
Daniel
D
Hoare
Sam R
SR
Madan
Ajay
A
Foster
Alan C
AC
Chen
Chen
C
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001823:Body Composition; D001835:Body Weight; D002100:Cachexia / Q000188:drug therapy*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C470072:MC4R protein, human; D011760:Pyrrolidinones; D044105:Receptor, Melanocortin, Type 4