Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25 as a potential treatment for Alzheimer's disease

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 22, 2004, Pages 5521-5525

  Helal, Christopher J ^a   Sanner, Mark A ^a   Cooper, Christopher B ^a   Gant, Thomas ^a   Adam, Mavis ^a   Lucas, John C ^a   Kang, Zhijun ^a   Kupchinsky, Stanley ^a   Ahlijanian, Michael K ^a   Tate, Bonnie ^a   Menniti, Frank S ^a   Kelly, Kristin ^a   Peterson, Marcia ^a  

^a PFIZER INC   (United States)

Author keywords

2 Aminothiazole; Alzheimer's disease; Cyclin E; Cyclin dependent kinase 2; Cyclin dependent kinase 5; p25

Indexed keywords

2 AMINOTHIAZOLE DERIVATIVE; N (5 ISOPROPYLTHIAZOL 2 YL)ISOBUTYRAMIDE; THIAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ARTICLE; DRUG POTENCY; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; HUMAN; IC 50; STRUCTURE ACTIVITY RELATION;

ALZHEIMER DISEASE; AMIDES; CDC2-CDC28 KINASES; CYCLIN-DEPENDENT KINASE 2; CYCLIN-DEPENDENT KINASE 5; CYCLIN-DEPENDENT KINASES; DRUG EVALUATION, PRECLINICAL; MOLECULAR STRUCTURE; NERVE TISSUE PROTEINS; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES;

EID: 5144230218     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.09.006     Document Type: Article

References (15)

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4. For recent articles describing 2-aminothiazole inhibitors of cdk2 see: K.S. Kim, S.D. Kimball, R.N. Misra, D.B. Rawlins, J.T. Hunt, H.-Y. Xiao, S. Lu, L. Qian, W.-C. Han, W. Shan, T. Mitt, Z.-W. Cai, M.A. Poss, H. Zhu, J.S. Sack, J.S. Tokarski, C.-Y. Chang, N. Pavletich, A. Kamath, W.G. Humphreys, P. Marathe, I. Bursuker, K.A. Kellar, U. Roongta, R. Batorsky, J.G. Mulheron, D. Bol, C. Fairchild, F.Y. Lee, and K.R. Webster J. Med. Chem. 45 2002 3905
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7. (a) Cooper, C. B.; Helal, C. J.; Sanner, M. A. EU Patent EP-1256578-A1, 2002
8. (b) Sanner, M. A.; Helal, C. J.; Cooper, C. B. US Patent U.S. 6,720,427 B2, 2004
9. (c) Pevarello, P.; Amica, R.; Villa, M.; Salom, B.; Vulpetti, A.; Varasi, M. U.S. Patent 372,832, 2000
10. (d) Pevarello, P.; Amici, R.; Traquandi, G.; Villa, M.; Vulpetti, A.; Isacchi, A. WO Patent 0026203, 2000
11. The kinase selectivity panel consisted of Akt-1, PKCα, phosphorylase kinase, lck, p70 S6K, p38δ, p38γ, p38β, p38, PRAK, ROKα, SGK, CKII, ChK1, PDK1, JNK, GSK3β, MAPK, RSK2, MSK1, PKA, MAPKAP kinase-2, AMPK, and MEK1. All assays were conducted in the presence of 100 μM ATP. Compound 1 showed less than 50% inhibition versus the kinases tested
12. A.R. Katritzky, K.S. Laurenzo, and D.I. Relyea Can. J. Chem. 66 1988 1617 1624
13. See Ref. 5a for detailed cdk5/p25 and cdk2/cyclin E assay methods
14. +, 100%
15. cdk5/p25 crystal structure ID code is 1h4L in the Protein Data Bank