| Structural highlights
Function
[BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2]
Publication Abstract from PubMed
Truncation of the S3 substituent of the biaryl aminothiazine 2, a potent BACE1 inhibitor, led to a low molecular weight aminothiazine 5 with moderate activity. Despite its moderate activity, compound 5 demonstrated significant brain Abeta reduction in rodents. The metabolic instability of 5 was overcome by the replacement of the 6-dimethylisoxazole, a metabolic soft spot, with a pyrimidine ring. Thus, truncation of the S3 substituent represents a viable approach to the discovery of orally bioavailable, brain-penetrant BACE1 inhibitors.
Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine beta-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors.,Wu YJ, Guernon J, Shi J, Marcin L, Higgins M, Rajamani R, Muckelbauer J, Lewis H, Chang C, Camac D, Toyn JH, Ahlijanian MK, Albright CF, Macor JE, Thompson LA J Med Chem. 2016 Sep 7. PMID:27559936[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
- ↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
- ↑ Wu YJ, Guernon J, Shi J, Marcin L, Higgins M, Rajamani R, Muckelbauer J, Lewis H, Chang C, Camac D, Toyn JH, Ahlijanian MK, Albright CF, Macor JE, Thompson LA. Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine beta-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors. J Med Chem. 2016 Sep 7. PMID:27559936 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01012
|
