title: 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.
abstract: 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.
authors.affiliation: CNS Discovery Research, AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, Wilmington, DE 19850-5437, USA. philip.edwards@astrazeneca.com
authors.forename: Philip D
authors.initials: PD
authors.lastname: Edwards
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Albert
authors.forename: Mark
authors.initials: M
authors.lastname: Sylvester
authors.forename: David
authors.initials: D
authors.lastname: Aharony
authors.forename: Donald
authors.initials: D
authors.lastname: Andisik
authors.forename: Owen
authors.initials: O
authors.lastname: Callaghan
authors.forename: James B
authors.initials: JB
authors.lastname: Campbell
authors.forename: Robin A
authors.initials: RA
authors.lastname: Carr
authors.forename: Gianni
authors.initials: G
authors.lastname: Chessari
authors.forename: Miles
authors.initials: M
authors.lastname: Congreve
authors.forename: Martyn
authors.initials: M
authors.lastname: Frederickson
authors.forename: Rutger H A
authors.initials: RH
authors.lastname: Folmer
authors.forename: Stefan
authors.initials: S
authors.lastname: Geschwindner
authors.forename: Gerard
authors.initials: G
authors.lastname: Koether
authors.forename: Karin
authors.initials: K
authors.lastname: Kolmodin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Krumrine
authors.forename: Russell C
authors.initials: RC
authors.lastname: Mauger
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Murray
authors.forename: Lise-Lotte
authors.initials: LL
authors.lastname: Olsson
authors.forename: Sahil
authors.initials: S
authors.lastname: Patel
authors.forename: Nate
authors.initials: N
authors.lastname: Spear
authors.forename: Gaochao
authors.initials: G
authors.lastname: Tian
mesh_terms: 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
chemical_list: D000578:Amidines; D008024:Ligands; D011743:Pyrimidines; C093270:isocytosine; D003596:Cytosine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human