Synthesis, SAR, and X-ray structure of human BACE-1 inhibitors with cyclic urea derivatives.
We describe synthesis and evaluation of a series of cyclic urea derivatives with hydroxylethylamine isostere. Modification of P3, P1, and P2' and combination of SAR display a >100-fold increase in potency with good cellular activity (IC(50)=0.15microM) relative to the previously reported compound 3.
Park
Heuisul
H
Drug Discovery, Research & Development, LG Life Sciences, 104-1 Munji-dong, Yuseong-gu, Daejon 305-380, Republic of Korea. renivie@lgls.com
Min
Kyeongsik
K
Kwak
Hyo-Shin
HS
Koo
Ki Dong
KD
Lim
Dongchul
D
Seo
Sang-Won
SW
Choi
Jae-Ung
JU
Platt
Bettina
B
Choi
Deog-Young
DY
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D018360:Crystallography, X-Ray; D003500:Cyclization; D005021:Ethylamines / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D020128:Inhibitory Concentration 50; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*
D005021:Ethylamines; D011480:Protease Inhibitors; D014508:Urea; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human