Second generation of BACE-1 inhibitors part 3: Towards non hydroxyethylamine transition state mimetics

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 13, 2009, Pages 3674-3678

  Charrier, Nicolas ^a   Clarke, Brian ^a   Cutler, Leanne ^a   Demont, Emmanuel ^a   Dingwall, Colin ^a   Dunsdon, Rachel ^a   Hawkins, Julie ^a   Howes, Colin ^a   Hubbard, Julia ^a   Hussain, Ishrut ^a   Maile, Graham ^a   Matico, Rosalie ^a   Mosley, Julie ^a   Naylor, Alan ^a   O'Brien, Alistair ^a   Redshaw, Sally ^a   Rowland, Paul ^a   Soleil, Virginie ^a   Smith, Kathrine J ^a   Sweitzer, Sharon ^a   Theobald, Pam ^a   Vesey, David ^a   Walter, Daryl S ^a   Wayne, Gareth ^a   more..

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

Alzheimer; Apartic protease; BACE 1; Hydroxyethylamine

Indexed keywords

ALKYL GROUP; BETA SECRETASE INHIBITOR; CYCLOPROPANE DERIVATIVE; INDOLE DERIVATIVE; KETONE DERIVATIVE; SULFONAMIDE;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DOG; DRUG ABSORPTION; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG PENETRATION; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SELECTIVITY; DRUG SYNTHESIS; MOUSE; NONHUMAN; PKA; STRUCTURE ACTIVITY RELATION;

AMYLOID BETA-PROTEIN; ANIMALS; ASPARTIC ENDOPEPTIDASES; BIOLOGICAL AVAILABILITY; DOGS; ETHYLAMINES; MICE; MICE, KNOCKOUT; P-GLYCOPROTEIN; PROTEASE INHIBITORS; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

ANIMALIA;

EID: 66349098289     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.03.149     Document Type: Article

References (19)

1. See:. Charrier N., Clarke B., Cutler L., Demont E., Dingwall C., Dunsdon R., Hawkins J., Howes C., Hussain I., Maile G., Matico R., Mosley J., Naylor A., O'Brien A., Redshaw S., Rowland P., Soleil V., Smith K.J., Sweitzer S., Theobald P., Vesey D., Walter D.W., and Wayne G. Bioorg. Med. Chem. Lett. 19 (2009) 3664
2. Charrier N., Clarke B., Demont E., Dingwall C., Dunsdon R., Hawkins J., Hussain I., Maile G., Matico R., Mosley J., Naylor A., O'Brien A., Redshaw S., Rowland P., Soleil V., Smith K.J., Sweitzer S., Theobald P., Vesey D., Walter D.W., and Wayne G. Bioorg. Med. Chem. Lett. 19 (2009) 3669
3. The tricyclic inhibitor used in this experiment was the hydroxyethylamine derivative bearing a pyrane as prime side substituent.
4. Clarke B., Demont E., Dingwall C., Dunsdon R., Faller A., Hawkins J., Hussain I., MacPherson D., Maile G., Matico R., Milner P., Mosley J., Naylor A., O'Brien A., Redshaw S., Riddell D., Rowland P., Soleil V., Smith K.J., Stanway S., Stemp G., Sweitzer S., Theobald P., Vesey D., Walter D.W., Ward J., and Wayne G. Bioorg. Med. Chem. Lett. 18 (2008) 1011
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6. The tricyclic sulfonates where synthesised in an analogous manner to the sulfonamide, using 7-hydroxy indoles as starting material. See:. Charrier N., Demont E., Dunsdon R., Maile G., Naylor A., O'Brien A., Redshaw S., Theobald P., Vesey D.S., and Walter D.W. Synthesis (2006) 3467
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13. In our hands, 2-F and 2,4-F phenyls are equipotent to the unsubstituted phenyl derivative.
14. Data for compound 16 have already been published in:. Charrier N., Clarke B., Cutler L., Demont E., Dingwall C., Dunsdon R., Hawkins J., Howes C., Hussain I., Maile G., Matico R., Mosley J., Naylor A., O'Brien A., Redshaw S., Rowland P., Soleil V., Smith K.J., Sweitzer S., Theobald P., Vesey D.S., Walter D.W., and Wayne G. J. Med. Chem. 51 (2008) 3313
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19. free = 0.224. For another example of amino ketones as BACE-1 inhibitors, see: Uchikawa, O.; Kazuyoshi, A.; Koike, T.; Tarui, N.; Hirai, K. Int. Appl. WO2004014843A1, 2004.