Identification and optimization of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)- yl)acetamide vasopressin V3 (V1b) receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 18, 2010, Pages 5394-5397

  Letourneau, Jeffrey J ^a   Riviello, Christopher M ^a   Li, Hong ^a   Cole, Andrew G ^a   Ho, Koc Kan ^a   Zanetakos, Heather A ^a   Desai, Hema ^a   Zhao, Jiuqiao ^a   Auld, Douglas S ^a   Napier, Susan E ^b   Thomson, Fiona J ^b   Goan, Katharine A ^b   Morphy, J Richard ^b   Ohlmeyer, Michael H J ^a   Webb, Maria L ^a  

^a Ligand Pharmaceuticals Inc   (United States)

^b MSD   (United Kingdom)

Author keywords

Antagonist; HPA axis; Quinazolinone; Vasopressin (V1b) receptor

Indexed keywords

2 [4 OXO 2 ARYL QUINAZOLIN 3(4H)YL]ACETAMIDE; UNCLASSIFIED DRUG; VASOPRESSIN RECEPTOR ANTAGONIST;

ARTICLE; BINDING ASSAY; DRUG BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; IC 50; PHYSICAL CHEMISTRY; STRUCTURE ACTIVITY RELATION;

ACETAMIDES; ANIMALS; DEPRESSIVE DISORDER; HUMANS; QUINAZOLINES; RATS; RECEPTORS, VASOPRESSIN; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 77956175953     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.07.118     Document Type: Article

References (30)

1. F. Holsboer, and N. Barden Endocr. Rev. 17 1996 187
2. N. Barden, J.M.H.M. Reul, and F. Holsboer TINS 18 1995 6
3. S. Scaccianoce, L.A.A. Muscolo, G. Cigliana, D. Navarra, R. Nicolai, and L. Angelucci Endocrinology 128 1991 3138
4. X.-M. Ma, A. Levy, and S.L. Lightman Endocrinology 138 1997 4351
5. A.F. Pitts, S.D. Samuelson, W.H. Meller, G. Bissette, C.B. Nemeroff, and R.G. Kathol Biol. Psych. 38 1995 330
6. C.B. Nemeroff Pharmacopsychiatry 21 1988 76
7. J.S. Purba, W.J.G. Hoogendijk, M.A. Hofman, and D.F. Swaab Arch. Gen. Psychiatry 53 1996 137
8. G. Griebel, J. Simiand, C. Serradeil-Le Gal, J. Wagnon, M. Pascal, B. Scatton, J.-P. Maffrand, and P. Soubrie PNAS 99 2002 6370
9. C. Serradeil-Le Gal, J. Wagnon, B. Tonnerre, R. Roux, G. Garcia, G. Griebel, and A. Aulombard CNS Drug Rev. 11 2005 53
10. For a recent review describing various vasopressin receptor agonists and antagonists, including SSR149415, see: T. Ryckmans Annu. Rep. Med. Chem. 44 2009 129
11. ClinicalTrials.gov web-based search. http://clinicaltrials.gov/ct2/search (accessed Jan 2008), 3 phase II trials listed using search term 'SSR149415'.
12. J.J. Baldwin, J.J. Burbaum, I. Henderson, and M.H.J. Ohlmeyer J. Am. Chem. Soc. 117 1995 5588
13. M.H.J. Ohlmeyer, R.N. Swanson, L.W. Dillard, J.C. Reader, G. Asouline, R. Kobayashi, M. Wigler, and W.C. Still Proc. Natl. Acad. Sci. U.S.A. 90 1993 10922
14. H.P. Nestler, P.A. Bartlett, and W.C. Still J. Org. Chem. 59 1994 4723
15. 3H]-AVP and 1% DMSO. The mixtures are incubated at room temperature for 30 min. The plates are washed twice with 100 μL/well (for 384-well plate) or 200 μL/well (for 96-well plate) of PBS and air dried. Detection is performed by adding 50 μL of scintillation fluid and shaking for 30 min followed by counting at 1 min/well in the microbeta.
16. A.M. Davies, D.J. Keeling, J. Steele, N.P. Tomkinson, and A.C. Tinker Curr. Top. Med. Chem. 5 2005 421
17. A. Alanine, M. Nettekoven, E. Roberts, and A.W. Thomas Comb. Chem. High Throughput Screening 6 2003 51
18. W.F. Michne Pharm. News 3 1996 19
19. C.A. Lipinski, F. Lombardo, B.W. Dominy, and P.J. Feeney Adv. Drug Delivery Rev. 23 1997 3
20. W.J. Egan, K.M. Merz, and J.J. Baldwin J. Med. Chem. 43 2000 3867
21. D.F. Veber, S.R. Johnson, H.Y. Cheng, B.R. Smith, and K.W. Ward J. Med. Chem. 45 2002 2615
22. Physicochemical properties calculated using ADME Profiler: Program for discreet compound analysis and calculation of physicochemical properties, version 1.6.0; Pharmacopeia Inc., 2004.
23. P.R. Andrews, D.J. Craik, and J.L. Martin J. Med. Chem. 27 1984 1648
24. Letourneau, J.; Riviello, C.; Ho, K.-K.; Chan, J.-H.; Ohlmeyer, M.; Jokiel, P.; Neagu, I.; Morphy, J. R.; Napier, S. E. 2-(4-oxo-4H-quinazolin-3-yl) Acetamides and their use as vasopressin V3 antagonists. PCT Int. Appl. WO 06095014, 2006.
25. First report: O. Mitsunobu, M. Yamada, and T. Mukaiyama Bull. Chem. Soc. Jpn. 40 1967 935
26. For reviews, see: O. Mitsunobu Synthesis 1981 1
27. D.L. Hughes Org. React. 42 1992 335
28. D.L. Hughes Org. Prep. Proced. Int. 28 1996 127
29. 3H]-oxytocin for human oxytocin receptor whole cell binding assay.
30. 2, 1 mg/mL BSA, and 0.5% DMSO). The assay mixture was incubated at room temperature for 60 min. The reaction was terminated by rapid filtration of the mixture over 96-well GF/B filters (pre-soaked in 0.3% polyethylenimine) using a Tomtec Harvester. The filters were washed four times with approximately 200 μL of ice-cold 50 mM Tris-HCl (pH 7.4), then dried at 55 °C for 30 min. 50 μL scintillation fluids were then added and the filters counted using a Packard Topcount.