Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity.
Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC(50) values of 1 and 2 nM and is not active (IC(50) > 25 μM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP(-/-) and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice.
Zhou
Changyou
C
Department of Medicinal Chemistry, Merck Research Laboratories,Rahway, New Jersey 07065, USA.
Garcia-Calvo
Margareta
M
Pinto
Shirly
S
Lombardo
Matthew
M
Feng
Zhe
Z
Bender
Kate
K
Pryor
Kellyann D
KD
Bhatt
Urmi R
UR
Chabin
Renee M
RM
Geissler
Wayne M
WM
Shen
Zhu
Z
Tong
Xinchun
X
Zhang
Zhoupeng
Z
Wong
Kenny K
KK
Roy
Ranabir Sinha
RS
Chapman
Kevin T
KT
Yang
Lihu
L
Xiong
Yusheng
Y
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C553300:2-amino-N-(3-(biphenyl-4-yl)-1-(2-(5,6-dichloro-1H-benzimidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-yl)-2-methylpropanamide; D019440:Anti-Obesity Agents; D001562:Benzimidazoles; D001798:Blood Proteins; D015842:Serine Proteinase Inhibitors; D010649:Phenylalanine; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase