Discovery of a new cyclooxygenase-2 lead compound through 3-D database searching and combinatorial chemistry

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 5, 1998, Pages 529-534

  Stewart, Kent D ^b   Loren, Stefan ^b   Frey, Lisa ^b   Otis, Ellen ^a   Klinghofer, Vered ^a   Hulkower, Keren I ^a  

^a ABBOTT LABORATORIES   (United States)

^b NONE

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFLAMMATORY AGENT; CYCLOOXYGENASE 2; CYCLOOXYGENASE 2 INHIBITOR; PHENOTHIAZINE;

ANTIINFLAMMATORY ACTIVITY; ARTICLE; CHEMISTRY; CONTROLLED STUDY; DATA BASE; DRUG DESIGN; DRUG SYNTHESIS; METHODOLOGY; NONHUMAN;

BINDING SITES; CYCLOOXYGENASE 2; DATABASE MANAGEMENT SYSTEMS; ISOENZYMES; PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES; PROTEIN CONFORMATION;

EID: 0032478056     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00068-7     Document Type: Article

References (13)

1. 1. Griswold, D. E.; Adams, J. L. Med. Res. Reviews 1996, 16, 181.
2. 2. Picot, D.; Loll, P. J.; Garavito, R. M. Nature 1994, 307, 243.
3. 3. DesJarlais, R.; Sheridan, R.; Seibel, G.; Dixon, J.; Kuntz, I.; Venkataraghavan, R. J. Med. Chem. 1988, 31, 722.
4. 4. Protein Data Base structure 1PRH was used directly in DOCK 3.0 searches with the shape-fitting algorithm. A database of a. 210 entries from the Cambridge Crystallographic Database, CSD, ranging from entries AACFAZ10 to BBETIM10 was searched allowing 3 close contacts per scoring orientation. Close contacts were permitted because of the uncertainty in the protein structure due to the low resolution (3.5 A°) data that was available. CSD entry APYANB, melitracene, was ranked 1 in the hit list and filled the void volume remarkably well.
5. 5. Shen, T. Y.; Ham, E. A.; Cirillo, V. J.; Zanetti, M. In Prostagandin Synthetase Inhibitors; Robinson, H. J.; Vane, J. R., Eds.; Raven: New York, 1974; pp 19-31.
6. 2 production by the reaction mixtures was measured by EIA (Cayman Chemicals, Ann Arbor, MI).
7. 7. Godefroi, E. F.; Wittle, E. I. J. Org. Chem. 1956, 21, 1163.
8. 8. A solution of 4.67 g 1-ethyl-3[3-(dimethylamino)propyl]-carbodiimide hydrochloride (24.37 mmol) and 0.975 g of 4-dimethylaminopyridine in 150 mL dichloromethane was partitioned among 48 various carboxylic acids in disposable 16 × 125 mm screw capped culture tubes (approx. twofold excess to the amount of compound 7). A solution of 2.50 g of 1-(3-aminopropyl)phenothiazine, 7, (9.75 mmol) in 100 mL dichloromethane was distributed equally among the tubes by a repeater pipette (2 mL each). The reactions were shaken at ambient temperature for 48 h. The reactions were washed with 5 mL × 2 portions of 1 M citric acid, 5 mL × 2 portions of 1/2 saturated sodium carbonate solution, and 5 mL × 2 portions of distilled water. After each wash, the tubes were shaken followed by centrifugation. The solvent was then removed by a Savant speedvac overnight. The residues were purified by column chromatography utilizing sep-packs filled with silica gel. The eluant used was solutions of ethyl acetate/dichloromethane of varying proportions. Purities obtained were determined by HPLC (88%-98%). Verification of the product was determined by MS. The yields ranged from 55-98%.
9. 9. All 48 carboxylic acids used in this library were commercially available, except the acid used in the synthesis of compound 11. In this case, 3-(p-bromophenoxy)-2,2-dimethylproprionic acid was prepared by p-bromophenoxide reaction with the mesylate of 2,2-dimethyl-3 hydroxyproprionic acid.
10. 3-phenyl; 3-phenoxypropyl; styryl; 2-fluorophenyl; 2,4,6-trimethylphenylmethyl; 2-(3-methoxyphenyl)ethyl; 4-methoxyphenylmethyl; 4-phenylbutyl; 4-pentynyl; 2-nitrophenylmethyl; 5-(methoxy)-5-oxo-pentyl; 4-bromophenylmethyl; 3-(methoxy)-3-oxo-propyl; 4-N,N-(dimethyl)-aminobenzyl; 3,4,5-trimethoxybenzyl. Three additional compounds proved too insoluble to assay.
11. 11. Luong, C.; Miller, A.; Barnett, J.; Chow, J.; Ramesha, C.; Browner, M. F. Nature Struct. Biol. 1996, 3, 927.
12. 12. Kick, E. K.; Roe, D. C.; Skillman, A. G.; Liu, G.; Ewing, T.; Sun, Y.; Kuntz, I. D.; Ellman, J. A. Chem. Biol. 1997, 4, 297.
13. 13. Lombardino, J. G. In Nonsteroidal Antiinflammatory Drugs; Lombardino, J. G., Ed.; Wiley, 1995; p 254.