Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency.
Fragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitors of beta-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution of these fragments using X-ray crystallography together with potency determination using surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around the isocytosine core led to the identification of a related series of inhibitors, the dihydroisocytosines. By leveraging the knowledge of the ligand-BACE-1 recognition features generated from the isocytosines, the dihydroisocytosines were efficiently optimized to submicromolar potency. Compound 29, with an IC50 of 80 nM, a ligand efficiency of 0.37, and cellular activity of 470 nM, emerged as the lead structure for future optimization.
Edwards
Philip D
PD
CNS Discovery Research, AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, Wilmington, DE 19850-5437, USA. philip.edwards@astrazeneca.com
Albert
Jeffrey S
JS
Sylvester
Mark
M
Aharony
David
D
Andisik
Donald
D
Callaghan
Owen
O
Campbell
James B
JB
Carr
Robin A
RA
Chessari
Gianni
G
Congreve
Miles
M
Frederickson
Martyn
M
Folmer
Rutger H A
RH
Geschwindner
Stefan
S
Koether
Gerard
G
Kolmodin
Karin
K
Krumrine
Jennifer
J
Mauger
Russell C
RC
Murray
Christopher W
CW
Olsson
Lise-Lotte
LL
Patel
Sahil
S
Spear
Nate
N
Tian
Gaochao
G
D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D002460:Cell Line; D018360:Crystallography, X-Ray; D003596:Cytosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000578:Amidines; D008024:Ligands; D011743:Pyrimidines; C093270:isocytosine; D003596:Cytosine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human