Identification, synthesis, and biological evaluation of novel pyrazoles as low molecular weight luteinizing hormone receptor agonists

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 7, 2007, Pages 2080-2085

  Jorand Lebrun, Catherine ^a   Brondyk, Bill ^b   Lin, Jing ^b   Magar, Sharad ^b   Murray, Robert ^b   Reddy, Adulla ^b   Shroff, Hitesh ^b   Wands, Greg ^b   Weiser, Weishui ^b   Xu, Qihong ^b   McKenna, Sean ^b   Brugger, Nadia ^b  

^a MERCK SERONO S A   (Switzerland)

^b EMD SERONO INC   (United States)

Author keywords

Gonadotropins; Luteinizing hormone receptor agonist; Regioselective pyrazole synthesis

Indexed keywords

CYCLIC AMP; HORMONE RECEPTOR STIMULATING AGENT; LUTEINIZING HORMONE RECEPTOR; LUTEINIZING HORMONE RECEPTOR AGONIST; PYRAZOLE DERIVATIVE; TESTOSTERONE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; CELL ASSAY; CHO CELL; CONTROLLED STUDY; DRUG ACTIVATION; DRUG ACTIVITY; DRUG IDENTIFICATION; DRUG SCREENING; DRUG SELECTIVITY; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; IN VITRO STUDY; IN VIVO STUDY; LEYDIG CELL; NONHUMAN; RAT; SOLID PHASE SYNTHESIS; STRUCTURE ACTIVITY RELATION;

ANIMALS; CHEMISTRY, PHARMACEUTICAL; CHO CELLS; CRICETINAE; CRICETULUS; DRUG DESIGN; LEYDIG CELLS; MALE; MOLECULAR CONFORMATION; MOLECULAR WEIGHT; PYRAZOLES; RATS; RECEPTORS, LH; STRUCTURE-ACTIVITY RELATIONSHIP; TESTOSTERONE;

RATTUS;

EID: 33847614837     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.12.062     Document Type: Article

References (19)

1. Erickson G.F., Magoffin D.A., Dyer C.A., and Hofeditz C. Endocr. Rev. 6 (1985) 371
2. Sharpe R.M. Clin. Endocrinol. 33 (1990) 787
3. Dufau M.L. Annu. Rev. Physiol. 60 (1998) 461
4. Jiang X., Dreano M., Buckler D.L., Cheng S., Ythier A., Wu H., Hendrickson W.A., and El Tayar N. Structure 3 (1995) 1341
5. El Tayar N. Mol. Cell. Endocrinol. 125 (1996) 65
6. Wrobel J., Green D., Jetter J., Kao W., Rogers J., Pérez M.C., Hardenburg J., Deecher D.C., López F.J., Brian J., Arey J.A., and Shen E.S. Bioorg. Med. Chem. 10 (2002) 639
7. Goutopoulos, A.; Reddy, A.; Liao, Y.; Magar, S.; Murray, R.; Weiser, W.; Nabioullin, R.; Rosenthal, J.; Buckler, D.; Cheng, S.; Liu, J.; McKenna, S.; Jiang, X.; Evans, D.; Tepper, M.; El Tayar, N. Abstracts of Papers, 226th National Meeting of the American Chemical Society, New York, NY, United States, September 7-11, 2003; American Chemical Society: Washington, DC, 2003; MEDI 365.
8. El Tayar, N.; Reddy, A.; Liao, Y.; Magar, S.; Murray, R.; Kozack, R.; Weiser, W.; Nabioullin, R.; Rosenthal, J.; Buckler, D.; Cheng, S.; Liu, J.; McKenna, S.; Jiang, X.; Evans, D.; Tepper, M.; Goutopoulos, A. Abstracts of Papers, 224th National Meeting of the American Chemical Society, Boston, MA, United States, August 18-22, 2002; American Chemical Society: Washington, DC, 2002; MEDI 355.
9. Palmer S.S., McKenna S., and Arkinstall S. RBM Online 10 (2005) 45
10. Van Straten N.C.R., Van Berkel T.H.J., Demont D.R., Karstens W.-J.F., Merkx R., Oosterom J., Schulz J., Van Someren R.G., Timmers C.M., and Van Zandvoort P.M. J. Med. Chem. 48 (2005) 1697
11. Van Straten N.C.R., Schoonus-Gerritsma G.G., Van Someren R.G., Draaijer J., Adang A.E.P., Timmers C.M., Hanssen R.G.J.M., and Van Boeckel C.A.A. ChemBioChem 10 (2002) 1023
12. Penning T.D., Talley J.J., Bertenshaw S.R., Carter J.S., Collins P.W., Docter S., Graneto M.J., Lee L.F., Malecha J.W., Miyashiro J.M., Rogers R.S., Rogier D.J., Yu S.S., Anderson G.D., Burton E.G., Cogburn J.N., Gregory S.A., Koboldt C.M., Perkins W.E., Seibert K., Veenhuizen A.W., Zhang Y.Y., and Isakson P.C. J. Med. Chem 40 (1997) 1347
13. 2 +8.9 (c 0.51, MeOH).
14. Stauffer S.R., Huang Y., Coletta C.J., Tedesco R., and Katzenellenbogen J.A. Bioorg. Med. Chem. 9 (2001) 141
15. Murray W.V. Tetrahedron Lett. 34 (1993) 1863
16. Compounds with purity lower than 60% by LC/MS were not considered.
17. Production cAMP in response to LH or small molecules was measured in CHO cells stably transfected with h-LH receptor. The cells were plated at a density of 20,000 cells/wells in growth medium (MEMalpha plus, 10% FBS, 1% l-glutamine, and 600 μg/ml Geneticin) in 96-well plates 1 day prior to the assay. Stimulation was carried out in assay buffer (phenol red-free DMEM/F12 containing 0.1% BSA, 0.1 mmol/L IBMX, and 1% pen-strep) for 60 min with increasing doses of test molecules. Following stimulation, cells were lysed and cAMP in the lysate was measured using a cAMP chemiluminescent assay kit (Tropix, Bedford, MA, USA) as per manufacturer's instructions.
18. 2 for 15 min. Cells were washed, plated at a density of 350,000 cells/well in 96-well plates (in phenol red-free DMEM/F12 media with 0.1% BSA), and stimulated with test compounds for 3 h. The plate was centrifuged to bring down the cells and 50 μL of culture media transferred to an ELISA plate (DSL) for testosterone measurement.
19. In vivo testosterone induction activity assay: on day 1, adult Sprague-Dawley rats were implanted subcutaneously in the scalpular region with a single 7-day slow-release pellet containing 7.5 mg of diethylstilbestrol (DES). After two days, rats were injected intraperitoneally with compound 10 at 0, 4, 16, or 32 mg/kg. Three rats were used in each treatment group. Blood samples were removed from the rat by retro-orbital plexus disruption after two hours following the administration. Serum was collected from blood by centrifugation and frozen at -80 °C until the time of assay. Serum testosterone concentrations and standard deviations were determined by ELISA and analyzed using Microsoft Excel software program.