Discovery of MK-5046, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity

Abstract

We report the development and characterization of compound 22 (MK-5046), a potent, selective small molecule agonist of BRS-3 (bombesin receptor subtype-3). In pharmacological testing using diet-induced obese mice, compound 22 caused mechanism-based, dose-dependent reductions in food intake and body weight.

Comparative Pharmacology of Bombesin Receptor Subtype-3, Nonpeptide Agonist MK-5046, a Universal Peptide Agonist, and Peptide Antagonist Bantag-1 for Human Bombesin Receptors

“…Our results differ from findings with the GRP/NMB receptors whose binding doseinhibition curves are best-fitted only by a single binding-site model (Mantey et al, 1993;Jensen et al, 2008) because we found that BRS-3-receptor exists in both a high-affinity and low-affinity state. Our results are similar to the previous studies that demonstrated that the nonpeptide agonist MK-5046 and the peptide antagonist-Bantag-1 have high affinity for hBRS-3 and that MK-5046 did not interact with either hGRP-R or hNMB-R even in the micromolar range (Guan et al, 2010;Sebhat et al, 2011). Our results differ from findings previously reported with Bantag-1 in which the antagonist was found to interact with both hGRP-R and hNMB-R in the micromolar range (Guan et al, 2010).…”

“…Peptide #1 had a more rapid onset and shorter duration of action for each. This difference was not due to a difference in stability with the two agonists, as previous studies had demonstrated that each is stable under incubation conditions at 37°C for at least 1 hour (Mantey et al, 1997;Sebhat et al, 2011;Reitman et al, 2012). Compared with previous studies that investigated the kinetics/duration of action of peptide and nonpeptide agonists, our results are similar to those with the CCK1-receptor nonpeptide agonist SR146131 (Bignon et al, 1999;Schaeffer et al, 2000), where the nonpeptide had a more prolonged duration of the action in stimulating [Ca 21 ] i when it was compared with an equally effective dose of the natural agonist CCK-8S.…”

“…In this study, we compared the ability of the naturally occurring Bn-related peptides GRP and NMB and the universal Bn-receptor agonist ligand peptide #1 (Mantey et al, 1997;Pradhan et al, 1998) to interact with and activate the three human Bnreceptor subtypes-hGRP-R, hNMB-R, and hBRS-3 -with that of MK-5046, a recently reported Sebhat et al, 2011) BRS-3-receptor selective nonpeptide agonist, and Bantag-1, a BRS-3 selective peptide antagonist (Guan et al, 2010;Feng et al, 2011). To be certain the results were reflective of the pharmacology of these peptides, two different Bn-receptor-containing cells were used to assess the results with each human Bn-receptor subtype.…”

“…Recent studies have reported that the nonpeptide MK-5046 [(2S)-1,1,1-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)propan-2-ol] is an orally active, potent, and selective BRS-3 agonist (Sebhat et al, 2011;Guan et al, 2011;Reitman et al, 2012), with activity in mice, rats, dogs , and humans (Reitman et al, 2012). Furthermore, recently a selective peptide antagonist Bantag-1 [Boc-Phe-His-4-amino-5-cyclohexyl-2,4,5-trideoxypentonyl-Leu-(3-dimethylamino) benzylamide N-methylammonium trifluoroacetate] also has been reported (Guan et al, 2010;Feng et al, 2011).…”

“…Furthermore, recently a selective peptide antagonist Bantag-1 [Boc-Phe-His-4-amino-5-cyclohexyl-2,4,5-trideoxypentonyl-Leu-(3-dimethylamino) benzylamide N-methylammonium trifluoroacetate] also has been reported (Guan et al, 2010;Feng et al, 2011). There are limited data on the pharmacologic characteristics of these compounds (Guan et al, 2010Feng et al, 2011;Sebhat et al, 2011). In addition, for the Bn-receptor family, similar to other gastrointestinal hormone/neurotransmitter G protein-coupled receptors, nonpeptide-agonists are uncommon (Freidinger, 1993;Jensen et al, 2008;Uehara et al, 2011); in fact, MK-5046 is the first high-affinity, widely used nonpeptide agonist for any member of the Bn family of receptors.…”