Potent, selective MCH-1 receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 4, 2008, Pages 1402-1406

  Erickson, Shawn D ^a   Banner, Bruce ^a   Berthel, Steven ^a   Conde Knape, Karin ^b   Falcioni, Fiorenza ^b   Hakimi, Irina ^b   Hennessy, Bernard ^a   Kester, Robert F ^a   Kim, Kyungjin ^a   Ma, Chun ^a   McComas, Warren ^a   Mennona, Francis ^a   Mischke, Steven ^a   Orzechowski, Lucy ^a   Qian, Yimin ^a   Salari, Hamid ^a   Tengi, John ^a   Thakkar, Kshitij ^a   Taub, Rebecca ^b   Tilley, Jefferson W ^a   Wang, Hong ^a   more..

^a HOFFMANN LA ROCHE INC   (United States)

^b Hoffman La Roche Department of Metabolic Diseases   (United States)

Author keywords

Antagonist; Indanylmethyl; MCHR1; Selectivity

Indexed keywords

ALPHA 2A ADRENERGIC RECEPTOR; DOPAMINE 3 RECEPTOR; DOPAMINE TRANSPORTER; KAPPA OPIATE RECEPTOR; MELANIN CONCENTRATING HORMONE RECEPTOR 1; MELANIN CONCENTRATING HORMONE RECEPTOR 1 ANTAGONIST; MU OPIATE RECEPTOR; NORADRENALIN TRANSPORTER; SEROTONIN 2C RECEPTOR; SEROTONIN TRANSPORTER; SOMATOSTATIN RECEPTOR 5;

ARTICLE; BODY WEIGHT; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG SELECTIVITY; FOOD INTAKE; HIGH THROUGHPUT SCREENING; IN VIVO STUDY; NONHUMAN; OBESITY;

AMIDES; ANIMALS; BENZIMIDAZOLES; CRYSTALLOGRAPHY, X-RAY; HUMANS; INDANS; KINETICS; PIPERIDINES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, SOMATOSTATIN; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 38949111737     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.01.010     Document Type: Article

References (32)

1. World Health Organization factsheet. Available from: http://www.who.int/dietphysicalactivity/publications/facts/obesity/en/.
2. United States Center for Disease Control and Prevention; Report on Overweight and Obesity. Available from: http://www.cdc.gov/nccdphp/dnpa/obesity/contributing_factors.htm.
3. Anand B.K., and Brobeck J.R. Yale J. Biol. Med. 24 (1951) 123
4. Neary M.L., Goldstone A.P., and Bloom S. Clin. Endocrinol. 60 (2004) 153
5. Jebb S.A., Siervo M., Fruehbeck G., Goldberg G.R., Murgatroyd P.R., and Prentice A.M. Int. J. Obes. 30 (2006) 1160
6. Seeley R.J., and Woods S.C. Nat. Rev. Neurosci. 4 (2003) 901
7. Kawauchi H., Kawazoe I., Tsubokawa M., Kishida M., and Baker B.I. Nature 305 (1983) 321
8. Saito Y., and Maruyama K. J. Exp. Zool. 305A (2006) 761
9. Chen Y., Hu C.i., Hsu C.-K., Zhang Q., Bi C., Asnicar M., Hsiung H.M., Fox N., Slieker L.J., Yang D.D., Heiman M.L., and Shi Y. Endocrinology 143 (2002) 2469
10. Marsh D.J., Weingarth D.T., Novi D.E., Chen H.Y., Trumbauer M.E., Chen A.S., Guan X.-M., Jiang M.M., Feng Y., Camacho R.E., Shen Z., Frazier E.G., Yu H., Metzger J.M., Kuca S.J., Shearman L.P., Gopal-Truter S., MacNeil D.J., Strack A.M., MacIntyre D.E., Van der Ploeg L.H.T., and Qian S. Proc. Natl. Acad. Sci. U.S.A. 99 (2002) 3080
11. Qu D., Ludwig D.S., Gammeltoft S., Piper M., Pelleymounter M.A., Cullen M.J., Mathes W.F., Przypek J., Kanarek R., and Maratos-Flier E. Nature 380 (1996) 243
12. Della-Zuana O., Presse F., Ortola C., Duhault J., Nahon J.L., and Levens N. Int. J. Obes. Relat. Metab. Disord. 26 (2002) 1289
13. Gomori A., et al. Am. J. Physiol. 284 (2003) E583
14. Whitlock B.K., Daniel J.A., McMahon C.D., Buonomo F.C., Wagner C.G., Steele B., and Sartin J.L. Domest. Anim. Endocrinol. 28 (2005) 224
15. Unmehopa U.A., van Heerikhuize J.J., Spijkstra W., Woods J.W., Howard A.D., Zycband E., Feighner S.D., Hreniuk D.L., Palyha O.C., Guan X.-M., MacNeil D.J., Van der Ploeg L.H.T., and Swaab D.F. J. Clin. Endocrinol. Metab. 90 (2005) 2412
16. Most recent reviews. Rokosz L.L., and Hobbs D.W. Drug News Perspect. 19 (2006) 273
17. McBriar M.D., and Kowalski T.J. Annu. Rep. Med. Chem. 40 (2005) 119
18. McBriar M.D. Curr. Opin. Drug Discov. Devel. 9 (2006) 496
19. Marzabadi, M. R.; Daniewska, I.; DeLeon, J.; Jiang, Y.; Lu, K.; Chen, C.-A.; Li, B.; Forray, C.; Borowsky, B.; Ogozalek, K.; Lichtblau, H.; Wetzel, J. M. Presented at the 224th Meeting of the American Chemical Society; Boston, MA, August 2002; MEDI-341.
20. Frimurer, T. M.; Ulven, T.; Hoegberg, T.; Norregaard, P. K.; Little, P. B.; Receveur, J.-M. WO/PCT2004052371
21. Lagu, B.; Wetzel, J.; Marzabadi, M. R.; Deleon, J. E.; Gluchowski, C.; Noble, S.; Nagarathnam, D.; Chiu, G. WO/PCT200206245.
22. Detailed protocols for each selectivity assay can be found at the MDS Panlabs website: http://discovery.mdsps.com/Catalog/Discovery/AssayPackage.aspx?id=104.
23. cf Doran et al. Drug Met. Dispos. 2005, 33, 165.
24. Sixty male Sprague-Dawley rats were placed on a high fat diet (60% calories from fat) from research diets at the age of 7 weeks. Animals were maintained on the diet for 7 weeks. One week before the start of the study rats were acclimated by dosing with 1 mL/kg of vehicle. Rats were sorted by body weight (BW) and single caged. Treatment started on day 0 and continued for 2 weeks. Animals were weighed and dosed daily according to BW. Compound 10 was formulated as a solution or suspension in 2% Klucel LF in water w/0.1% Tween 80 and administered at the target dose level (3, 10, 30 mg/kg po bid). For animals in the efficacy arm of the study (n = 9 per treatment group), food intake was recorded every day for the first four days and then twice per week.
25. Kim B.J., Pyun D.K., Jung H.J., Kwak H.J., Kim J.H., Kim E.J., Jeong W.J., and Lee C.H. Synth. Commun. 317 (2001) 1081
26. 3OH; 70 mL/min flowrate; 400 mg injections; 36 runs; 8 min cycles; 100 BAR back pressure; detection at 220 nM; 35 °C oven temperature.
27. cf Ridley, H. F.; Spickett; R. G. W.; Timmis, G. M. J. Heterocycl. Chem. 1965, 2, 453.
28. 2 with trace of water gave X-ray quality crystals of 4-[2,5-dimethylbenzimidazolyl]-Boc-piperidine. Accession No. CCDC667060.
29. Romero, A.; Leiby, J. A. U.S. Patent Appl. 1999, US5936000. We found that even minor deviations from the solvent ratio reported by the authors resulted in lower yield and enantioselectivity.
30. Klapars A., Huang X., and Buchwald S.L. J. Am. Chem. Soc. 124 (2002) 7421
31. cf Pooley, C. L. F.; Edwards, J. P.; Goldman, M. E.; Wang, M.-W.; Marschke, K. B.; Crombie, D. L.; Jones, T. K. J. Med. Chem. 1998, 41, 3461.
32. Description of hERG test protocol. Guo L., and Guthrie H. J. Pharmacol. Toxicol. Methods 52 (2005) 123