Literature summary for 3.4.23.46 extracted from

Hamada, Y.; Igawa, N.; Ikari, H.; Ziora, Z.; Nguyen, J.T.; Yamani, A.; Hidaka, K.; Kimura, T.; Saito, K.; Hayashi, Y.; Ebina, M.; Ishiura, S.; Kiso, Y.
beta-Secretase inhibitors: modification at the P4 position and improvement of inhibitory activity in cultured cells (2006), Bioorg. Med. Chem. Lett., 16, 4354-4359.

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Application

Application	Comment	Organism
pharmacology	design of inhibitor drugs for treatment of Alzheimer disease	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
conformational study of BACE1 inhibitor shown, molecular surface model and stereoview indicated	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
(2S,5S,8S,11S,14S)-14-amino-5-benzyl-8-(cyclohexylmethyl)-16-(5-fluoro-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-2-hydroxy-11-(1-methylethyl)-4,7,10,13,16-pentaoxo-N-[3-(2H-tetrazol-5-yl)phenyl]-3,6,9,12-tetraazahexadecan-1-amide	i.e. KMI-574, 100% and 97% inhibition at 2 microM and 0.2 microM, respectively, 84% inhibition of beta-secretase BACE1 in cultured cell-based assay at 100 microM	Homo sapiens
additional information	structures of BACE1 inhibitors containing a tetrazole ring at the P4 position indicated, inhibitory activities summarized	Homo sapiens

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P56817	-	-

Purification (Commentary)

Purification (Comment)	Organism
SDS-PAGE	Homo sapiens

Source Tissue

Source Tissue	Comment	Organism	Textmining
HEK-293 cell	stably expressing human BACE1 enzyme, used for inhibition assay	Homo sapiens	-

Specific Activity [micromol/min/mg]

Specific Activity Minimum [µmol/min/mg]	Specific Activity Maximum [µmol/min/mg]	Comment	Organism
additional information	-	BACE1 inhibitors generated by 9-fluorenylmethoxycarbonyl-solid-phase peptide synthesis methods, characterization of BACE1 inhibitor KMI-574, generation by replacement of acidic tetrazole ring with hydrogen bond acceptor group indicated, potent inhibitory activity in cultured cells as well as in vitro enzymatic assay shown, inhibitory activities summarized	Homo sapiens

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
((7-methoxycoumarin-4-yl)acetyl)-Ser-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-Lys(2,4-dinitrophenyl)-Arg-Arg-NH2 + H2O	synthesis, structure and potencies of beta-secretase BACE1 inhibitors optimized, effects of P4 modification on BACE1 inhibitory activity analyzed	Homo sapiens	((7-methoxycoumarin-4-yl)acetyl)-Ser-Glu-Val-Asn-Leu + Asp-Ala-Glu-Phe-Lys(2,4-dinitrophenyl)-Arg-Arg-NH2	-	?

Synonyms

Synonyms	Comment	Organism
BACE1	-	Homo sapiens
beta-secretase	-	Homo sapiens
beta-site APP (amyloid precursor protein) cleaving enzyme	-	Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
37	-	cellular inhibition assay at	Homo sapiens

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor	Structure
0.0056	-	i.e. KMI-574, used as a substrate transition-state mimic	Homo sapiens	(2S,5S,8S,11S,14S)-14-amino-5-benzyl-8-(cyclohexylmethyl)-16-(5-fluoro-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-2-hydroxy-11-(1-methylethyl)-4,7,10,13,16-pentaoxo-N-[3-(2H-tetrazol-5-yl)phenyl]-3,6,9,12-tetraazahexadecan-1-amide

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Release 2023.1 (January 2023)