Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 10, 2010, Pages 3158-3160

  Huang, Yifang ^a   Strobel, Eric D ^a   Ho, Chih Y ^a   Reynolds, Charles H ^a   Conway, Kelly A ^a   Piesvaux, Jennifer A ^a   Brenneman, Douglas E ^a   Yohrling, George J ^a   Moore Arnold, H ^a   Rosenthal, Daniel ^a   Alexander, Richard S ^a   Tounge, Brett A ^a   Mercken, Marc ^b   Vandermeeren, Marc ^b   Parker, Michael H ^a   Reitz, Allen B ^a   Baxter, Ellen W ^a  

^a JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

^b JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

Author keywords

Alzheimer's disease; BACE; BACE inhibitors

Indexed keywords

BETA SECRETASE INHIBITOR; MACROCYCLIC COMPOUND;

ALZHEIMER DISEASE; ANIMAL CELL; ARTICLE; CHEMICAL MODIFICATION; CHEMICAL REACTION; CHO CELL; CONTROLLED STUDY; DRUG POTENCY; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVE SITE; FEMALE; IC 50; NONHUMAN; PROCESS OPTIMIZATION; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

AMYLOID PRECURSOR PROTEIN SECRETASES; ASPARTIC ACID ENDOPEPTIDASES; BINDING SITES; COMPUTER SIMULATION; HUMANS; MACROCYCLIC COMPOUNDS; PROTEASE INHIBITORS; QUINAZOLINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 77952320391     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.03.097     Document Type: Article

References (32)

1. Goedert M., and Spillantini M.G. Science 314 (2006) 777
2. Roberson E.D., and Mucke L. Science 314 (2006) 781
3. Giacobini E., and Becker R.E. J. Alzheimer Dis. 12 (2007) 37
4. Robichaud A.J. Curr. Top. Med. Chem. 6 (2006) 553
5. Churcher I. Curr. Top. Med. Chem. 6 (2006) 579
6. Catalano S.M., Dodson E.C., Henze D.A., Joyce J.G., Krafft G.A., and Kinney G.G. Curr. Top. Med. Chem. 6 (2006) 597
7. Silvestri R. Med. Res. Rev. 29 (2009) 295
8. Stockley J.H., and O'Neill C. Cellu. Mol. Life Sci. 65 (2008) 3265
9. Ghosh A.K., Gemma S., and Tang J. Neurotherapeutics 5 (2008) 399
10. Venugopal C., Demos C.M., Rao K.S.J., Pappolla M.A., and Sambamurti K.C.N.S. Neurol. Disord. Drug Targets 7 (2008) 278
11. Olson R.E., and Marcin L.R. Annu. Rep. Med. Chem. 42 (2007) 27
12. Hills I.D., and Vacca J.P. Curr. Opin. Drug Discovery Dev. 10 (2007) 383
13. Nishitomi K., Sakaguchi G., Horikoshi Y., Gray A.J., Maeda M., Hirata-Fukae C., Becker A.G., Hosono M., Sakaguchi I., Minami S.S., Nakajima Y., Li H.-F., Takeyama C., Kihara T., Ota A., Wong P.C., Aisen P.S., Kato A., Kinoshita N., and Matsuoka Y. Neurochemistry 99 (2006) 1555
14. Luo Y., Bolon B., Damore M.A., Fitzpatrick D., Liu H., Zhang J., Yan Q., Vassar R., and Citron M. Neurobiol. Dis. 14 (2003) 81 and references cited therein
15. Hu X., Hicks C.W., He W., Wong P., Macklin W.B., Trapp B.D., and Yan R. Nat. Neurosci. 9 (2006) 1520
16. Laird F.M., Cai H., Savonenko A.V., Farah M.H., He K., Melnikova T., Wen H., Chiang H.-C., Xu G., Koliatsos V.E., Borchelt D.R., Price D.L., Lee H.-K., and Wong P.C. J. Neurosci. 25 (2005) 11693
17. Dominguez D., Tournoy J., Hartmann D., Huth T., Cryns K., Deforce S., Serneels L., Camacho I.E., Marjaux E., Craessaerts K., Roebroeck A.J.M., Schwake M., D'Hooge R., Bach P., Kalinke U., Moechars D., Alzheimer C., Reiss K., Saftig P., and De Strooper B. J. Biol. Chem. 280 (2005) 30797
18. Ohno M., Sametsky E.A., Younkin L.H., Oakley H., Younkin S.G., Citron M., Vassar R., and Disterhoft J.F. Neuron 41 (2004) 27
19. Sankaranarayanan S., Holahan M.A., Colussi D., Crouthamel M.-C., Devanarayan V., Ellis J., Espeseth A., Gates A.T., Graham S.L., Gregro A.R., Hazuda D., Hochman J.H., Holloway K., Jin L., Kahana J., Lai M.-T., Lineberger J., McGaughey G., Moore K.P., Nantermet P., Pietrak B., Price E.A., Rajapakse H., Stauffer S., Steinbeiser M.A., Seabrook G., Selnick H.G., Shi X.-P., Stanton M.G., Swestock J., Tugusheva K.S., Tyler K.X., Vacca J.P., Wong J., Wu G., Xu M., Cook J.J., and Simon A.J. J. Pharmacol. Exp. Ther. 328 (2009) 131
20. Meredith Jr. J.E., Thompson L.A., Toyn J.H., Marcin L., Barten D.M., Marcinkeviciene J., Kopcho L., Kim Y., Lin A., Guss V., Burton C., Iben L., Polson C., Cantone J., Ford M., Drexler D., Fiedler T., Lentz K.A., Grace Jr. J.E., Kolb J., Corsa J., Pierdomenico M., Jones K., Olsen R.E., Macor J.E., and Albright C.F. J. Pharmacol. Exp. Ther. 326 (2008) 502
21. Barrow J.C., Stauffer S.R., Rittle K.E., Ngo P.L., Yang Z., Selnick H.G., Graham S.L., Munshi S., McGaughey G.B., Holloway M.K., Simon A.J., Price E.A., Sankaranarayanan S., Colussi D., Tugusheva K., Lai M.-T., Espeseth A.S., Xu M., Huang Q., Wolfe A., Pietrak B., Zuck P., Levorse D.A., Hazuda D., and Vacca J.P. J. Med. Chem. 51 (2008) 6259
22. Ghosh A.K., Kumaragurubaran N., Hong L., Kulkarni S., Xu X., Miller H.B., Reddy D.S., Weerasena V., Turner R., Chang W., Koelsch G., and Tang J. Bioorg. Med. Chem. Lett. 18 (2008) 1031
23. Stanton M.G., Stauffer S.R., Gregro A.R., Steinbeiser M., Nantermet P., Sankaranarayanan S., Price E.A., Wu G., Crouthamel M.-C., Ellis J., Lai M.-T., Espeseth A.S., Shi X.-P., Jin L., Colussi D., Pietrak B., Huang Q., Xu M., Simon A.J., Graham S.L., Vacca J.P., and Selnick H. J. Med. Chem. 50 (2007) 3431
24. Ghosh A.K., Kumaragurubaran N., Hong L., Kulkarni S.S., Xu X., Chang W., Weerasena V., Turner R., Koelsch G., Bilcer G., and Tang J. J. Med. Chem. 50 (2007) 2399
25. Hussain I., Hawkins J., Harrison D., Hille C., Wayne G., Cutler L., Buck T., Walter D., Demont E., Howes C., Naylor A., Jeffrey P., Gonzalez M.I., Dingwall C., Michel A., Redshaw S., and Davis J.B. J. Neurochem. 100 (2007) 802
26. Stachel S.J., Coburn C.A., Sankaranarayanan S., Price E.A., Pietrak B.L., Huang Q., Lineberger J., Espeseth A.S., Jin L., Ellis J., Holloway M.K., Munshi S., Allison T., Hazuda D., Simon A.J., Graham S.L., and Vacca J.P. J. Med. Chem. 49 (2006) 6147
27. Asai M., Hattori C., Iwata N., Saido T.C., Sasagawa N., Szabó B., Hashimoto Y., Maruyama K., Tanuma S., Kiso Y., and Ishiura S. J. Neurochem. 96 (2006) 533
28. Chang W.-P., Koelsch G., Wong S., Downs D., Da H., Weerasena V., Gordon B., Devasamudram T., Bilcer G., Ghosh A.K., and Tang J. J. Neurochem. 89 (2004) 1409
29. Baxter E.W., Conway K.A., Kennis L., Bischoff F., Mercken M.H., De Winter H.L., Reynolds C.H., Tounge B.A., Luo C., Scott M.K., Huang Y., Braeken M., Pieters S.M.A., Berthelot D.J.C., Masure S., Bruinzeel W.D., Jordan A.D., Parker M.H., Boyd R.E., Qu J., Qu J., Qu J., Brenneman D.E., and Reitz A.B. J. Med. Chem. 50 (2007) 4261
30. Ghosh A.K., Shin D., Downs D., Koelsch G., Lin X., Ermolieff J., and Tang J. J. Am. Chem. Soc. 122 (2000) 3522
31. Jorgensen W.L., and Tirado-Rives J. J. Am. Chem. Soc. 110 (1988) 1657
32. When macrocycle 7 was dosed orally in non-transgenic mice, a statistically significant effect on Aβ lowering in plasma was observed: 23%, 22%, and 13%, at 50 mg/kg, 25 mg/kg, and 10 mg/kg dose, respectively, in 10% solutol.