Discovery of MK-5046, a potent, selective bombesin receptor subtype-3 agonist for the treatment of obesity

ACS Medicinal Chemistry Letters

Volumn 2, Issue 1, 2011, Pages 43-47

  Sebhat, Iyassu K ^a   Franklin, Christopher ^a   Lo, Michael M C ^a   Chen, David ^a   Jewell, James P ^a   Miller, Randy ^a   Pang, Jianmei ^a   Palyha, Oksana ^a   Kan, Yanqing ^a   Kelly, Theresa M ^a   Guan, Xiao Ming ^a   Marsh, Donald J ^a   Kosinski, Jennifer A ^a   Metzger, Joseph M ^a   Lyons, Kathryn ^a   Dragovic, Jasminka ^a   Guzzo, Peter R ^b   Henderson, Alan J ^b   Reitman, Marc L ^a   Nargund, Ravi P ^a   Wyvratt, Matthew J ^a   Lin, Linus S ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b ALBANY MOLECULAR RESEARCH INC   (United States)

Author keywords

bombesin receptor subtype 3 agonist; MK 5046; obesity

Indexed keywords

ANTIOBESITY AGENT; BOMBESIN RECEPTOR; MK 5046; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; BODY WEIGHT; DIETARY INTAKE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG STABILITY; DRUG STRUCTURE; FOOD INTAKE; METABOLIC RATE; MOUSE; NONHUMAN; OBESITY; PRIORITY JOURNAL; RAT; STRUCTURE ACTIVITY RELATION;

BOVINE RESPIRATORY SYNCYTIAL VIRUS; MUS;

EID: 78651474862     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml100196d     Document Type: Article

References (16)

1. Jensen, R. T.; Battey, J. F.; Spindel, E. R.; Benya, R. V. Mammalian bombesin receptors: Nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states Pharmacol. Rev. 2008, 60, 1-42
2. Battey, J.; Wada, E. Two distinct receptor subtypes for mammalian bombesin-like peptides Trends Neurosci. 1991, 14, 524-528
3. Fathi, Z.; Corjay, M. H.; Shapira, H.; Wada, E.; Benya, R.; Jensen, R.; Viallet, J.; Sausville, E. A.; Battey, J. F. BRS3: A novel bombesin receptor subtype selectively expressed in testis and lung carcinoma cells J. Biol. Chem. 1993, 268, 5979-5984
4. Ohki-Hamazaki, H.; Watase, K.; Yamamoto, K.; Ogura, H.; Yamano, M.; Yamada, K.; Maeno, H.; Imaki, J.; Kikuyama, S.; Wada, E.; Wada, K. Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity Nature 1997, 390, 165-169
5. Boyle, R. G.; Humphries, J.; Mitchell, T.; Showell, G. A.; Apaya, R.; Iijima, H.; Shimada, H.; Arai, T.; Ueno, H.; Usui, Y.; Sakaki, T.; Wada, E.; Wada, K. The design of a new potent and selective ligand for the orphan bombesin receptor subtype 3 (BRS3) J. Pept. Sci. 2005, 11, 136-141 and references therein
6. Weber, D.; Berger, C.; Heinrich, T.; Eickelmann, P.; Antel, J.; Kessler, H. Systematic optimization of a lead-structure identities for a selective short peptide agonist for the human orphan receptor BRS-3 J. Pept. Sci. 2002, 8, 461-475
7. Weber, D.; Berger, C.; Eickelmann, P.; Antel, J.; Kessler, H. Design of Selective Peptidomimetic Agonists for the Human Orphan Receptor BRS-3 J. Med. Chem. 2003, 46, 1918-1930
8. Carlton, D. L.; Collin-Smith, L. J.; Daniels, A. J.; Deaton, D. N.; Goetz, A. S.; Laudeman, C. P.; Littleton, T. R.; Musso, D. L.; Ott Morgan, R. J.; Szewczyk, J. R.; Zhang, C. Discovery of small molecule agonists for the bombesin receptor subtype 3 (BRS-3) based on an omeprazole lead Bioorg. Med. Chem. Lett. 2008, 18, 5451-5455
9. Guo, C.; Guzzo, P. R.; Hadden, M.; Sargent, B.; Yet, L.; Kan, Y.; Palyha, O.; Kelly, T. M.; Guan, X.-M.; Rosko, K.; Gagen, K.; Metzger, J. M.; Dragovic, J.; Lyons, K.; Lin, L. S.; Nargund, R. P. Synthesis of 7-benzyl-5-(piperidin-1- yl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]-[2,7]naphthyridin-1ylamine and its analogs as bombesin receptor subtype-3 agonists Bioorg. Med. Chem. Lett. 2010, 20, 2785
10. He, S.; Dobbelaar, P. H.; Liu, J.; Jian, T.; Sebhat, I. K.; Lin, L. S.; Goodman, A.; Guo, C.; Guzzo, P. R.; Hadden, M.; Henderson, A. J.; Ruenz, M.; Sargent, B.; Yet, L.; Kelly, T. M.; Palyha, O.; Kan, Y.; Pan, J.; Chen, H.; Marsh, D.; Shearman, L. P.; Strack, A. M.; Metzger, J. M.; Feighner, S. D.; Tan, C.; Howard, A. D.; Tamvakopoulos, C.; Peng, Q.; Guan, X.-M.; Reitman, M. L.; Patchett, A. A.; Wyvratt, M. J.; Nargund, R. P. Discovery of substituted biphenyl imidazoles as potent bioavailable bombesin receptor subtype-3 agonists Bioorg. Med. Chem. Lett. 2010, 20, 1913-1917
11. Liu, J.; He, S.; Jian, T.; Dobbelaar, P. H.; Sebhat, I. K.; Lin, L. S.; Goodman, A.; Guo, C.; Guzzo, P. R.; Hadden, M.; Henderson, A. J.; Pattamana, K.; Ruenz, M.; Sargent, B.; Swenson, B.; Yet, L.; Tamvakopoulos, C.; Peng, Q.; Pan, J.; Kan, Y.; Palyha, O.; Kelly, T. M.; Guan, X.-M.; Howard, A. D.; Marsh, D.; Metzger, J.; Reitman, M. L.; Wyvratt, M. J.; Nargund, R. P. Synthesis and SAR of derivatives based on 2-biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the treatment of obesity Bioorg. Med. Chem. Lett. 2010, 20, 2074-2077
12. Hadden, M.; Goodman, A.; Guo, C.; Guzzo, P. R.; Henderson, A. J.; Pattamana, K.; Ruenz, M.; Sargent, B.; Swenson, B.; Yet, L.; Liu, J.; He, S.; Sebhat, I. K.; Lin, L. S.; Tamvakopoulos, C.; Peng, Q.; Kan, Y.; Palyha, O.; Kelly, T. M.; Guan, X.-M.; Metzger, J.; Reitman, M. L.; Nargund, R. P. Synthesis and SAR of heterocyclic carboxylic acid isosteres based on 2- biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the treatment of obesity Bioorg. Med. Chem. Lett. 2010, 20, 2912-2915
13. Guan, X.-M.; Chen, H.; Dobbelaar, P. H.; Dong, Y.; Fong, T. M.; Gagen, K.; Gorski, J.; He, S.; Howard, A. D.; Jian, T.; Jiang, M.; Kan, Y.; Kelly, T. M.; Kosinski, J.; Lin, L. S.; Liu, J.; Marsh, D.; Metzger, J. M.; Miller, R.; Nargund, R. P.; Palyha, O.; Shearman, L.; Shen, Z.; Stearns, R.; Strack, A. M.; Stribling, S.; Tang, Y. S.; Wang, S.-P.; White, A.; Yu, H.; Reitman, M. L. Regulation of energy homeostasis by bombesin receptor subtype-3: Selective receptor agonists for the treatment of obesity Cell Metab. 2010, 11, 101-112
14. Absolute stereochemistry was determined via X-ray crystallography of the hydrochloride salt of an iodinated analogue ((2 S)-1,1,1-trifluoro-3-(5-iodo-4- {[1-(trifluoromethyl)cyclopropyl]methyl}-1 H -imidazol-2-yl)-2-[4-(1 H -pyrazol-1-yl)phenyl]propan-2-ol). Crystals of this salt were grown by evaporation of an EtOAc/hexane solution over a period of approximately 1 week. Diffraction data were measured at room temperature. Examination of the intermolecular distances to the Cl ion as well as the electron density maps indicates the protonation by HCl to form the salt occurs at N23. With the presence of the two heavy atoms in the lattice, determination of the absolute configuration at the chiral C (C1, S) was unambiguous.
15. 2+ was measured in HEK293AEQ cells overexpressing BRS-3, using an aequorin bioluminescence assay.
16. Guan, X.-M. Manuscript submitted.