Orally active and brain permeable proline amides as highly selective 5HT2c agonists for the treatment of obesity.
Brain-penetrable proline amides were developed as 5HT2c agonists with more than 1000-fold binding selectivity against 5HT2b receptor. After medicinal chemistry optimization and SAR studies, orally active proline amides with robust efficacy in a rodent food intake inhibition model were uncovered.
Liu
Kevin K-C
KK
Pfizer Global Research and Development, Chemistry Department, 10770 Science Center Drive, La Jolla, CA 92120, United States. kevin.k.liu@pfizer.com
Lefker
Bruce A
BA
Dombroski
Mark A
MA
Chiang
Phoebe
P
Cornelius
Peter
P
Patterson
Terrell A
TA
Zeng
Yuan
Y
Santucci
Stephanie
S
Tomlinson
Elizabeth
E
Gibbons
Colleen P
CP
Marala
Ravi
R
Brown
Janice A
JA
Kong
Jimmy X
JX
Lee
Eunsun
E
Werner
Wendy
W
Wenzel
Zane
Z
Giragossian
Craig
C
Chen
Hou
H
Coffey
Steven B
SB
D000284:Administration, Oral; D000577:Amides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D019440:Anti-Obesity Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D004285:Dogs; D004435:Eating / Q000187:drug effects; D006801:Humans; D009765:Obesity / Q000188:drug therapy*; D011392:Proline / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D013329:Structure-Activity Relationship
D000577:Amides; D019440:Anti-Obesity Agents; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D011392:Proline