TY - JOUR
T1 - Backbone cyclic peptidomimetic melanocortin-4 receptor agonist as a novel orally administrated drug lead for treating obesity
AU - Hess, Shmuel
AU - Linde, Yaniv
AU - Ovadia, Oded
AU - Safrai, Eli
AU - Shalev, Deborah E.
AU - Swed, Avi
AU - Halbfinger, Efrat
AU - Lapidot, Tair
AU - Winkler, Ilan
AU - Gabinet, Yael
AU - Faier, Avi
AU - Yarden, Dana
AU - Xiang, Zhimin
AU - Portillo, Federico P.
AU - Haskell-Luevano, Carrie
AU - Gilon, Chaim
AU - Hoffman, Amnon
PY - 2008/2/28
Y1 - 2008/2/28
N2 - The tetrapeptide sequence His-Phe-Arg-Trp, derived from melanocyte-stimulating hormone (αMSH) and its analogs, causes a decrease in food intake and elevates energy utilization upon binding to the melanocortin-4 receptor (MC4R). To utilize this sequence as an effective agent for treating obesity, we improved its metabolic stability and intestinal permeability by synthesizing a library of backbone cyclic peptidomimetic derivatives. One analog, peptide 1 (BL3020-1), was selected according to its selectivity in activating the MC4R, its favorable transcellular penetration through enterocytes and its enhanced intestinal metabolic stability. This peptide was detected in the brain following oral administration to rats. A single oral dose of 0.5 mg/kg in mice led to reduced food consumption (up to 48% vs the control group) that lasted for 5 h. Repetitive once daily oral dosing (0.5 mg/kg/day) for 12 days reduced weight gain. Backbone cyclization was shown to produce a potential drug lead for treating obesity.
AB - The tetrapeptide sequence His-Phe-Arg-Trp, derived from melanocyte-stimulating hormone (αMSH) and its analogs, causes a decrease in food intake and elevates energy utilization upon binding to the melanocortin-4 receptor (MC4R). To utilize this sequence as an effective agent for treating obesity, we improved its metabolic stability and intestinal permeability by synthesizing a library of backbone cyclic peptidomimetic derivatives. One analog, peptide 1 (BL3020-1), was selected according to its selectivity in activating the MC4R, its favorable transcellular penetration through enterocytes and its enhanced intestinal metabolic stability. This peptide was detected in the brain following oral administration to rats. A single oral dose of 0.5 mg/kg in mice led to reduced food consumption (up to 48% vs the control group) that lasted for 5 h. Repetitive once daily oral dosing (0.5 mg/kg/day) for 12 days reduced weight gain. Backbone cyclization was shown to produce a potential drug lead for treating obesity.
UR - http://www.scopus.com/inward/record.url?scp=39749193898&partnerID=8YFLogxK
U2 - 10.1021/jm701093y
DO - 10.1021/jm701093y
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C2 - 18220330
AN - SCOPUS:39749193898
SN - 0022-2623
VL - 51
SP - 1026
EP - 1034
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 4
ER -