Rational design and synthesis of potent dibenzazepine motifs as beta-secretase inhibitors.
We have identified small-molecule dibenzazepine inhibitors of beta-secretase (BACE1). These BACE1 inhibitors possess two key salient features. The first is a seven-membered heterocyclic ring fused to two aromatic rings representing the P3-P2 residues. The second is an amide and/or amide bioisostere representing the P1' residue. Rational optimization led to the identification of potent analogues, such as 10 (K(I) = 211 nM).
Al-Tel
Taleb H
TH
College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, UAE. taltal@sharjah.ac.ae
Al-Qawasmeh
Raed A
RA
Schmidt
Marco F
MF
Al-Aboudi
Amal
A
Rao
Shashidhar N
SN
Sabri
Salim S
SS
Voelter
Wolfgang
W
D000577:Amides / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D003984:Dibenzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D007093:Imidazoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D010795:Phthalic Acids / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000577:Amides; D003984:Dibenzazepines; D007093:Imidazoles; D010795:Phthalic Acids; D011480:Protease Inhibitors; C059768:isophthalate; C029899:imidazole; D053829:Amyloid Precursor Protein Secretases; C527817:dibenzazepine