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4JOO

Spirocyclic Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors

Summary for 4JOO
Entry DOI10.2210/pdb4joo/pdb
Related4JP9 4JPC 4JPE
DescriptorBeta-secretase 1, NICKEL (II) ION, (4R)-2'-amino-6-bromo-1',2,2-trimethyl-2,3-dihydrospiro[chromene-4,4'-imidazol]-5'(1'H)-one, ... (4 entities in total)
Functional Keywordsaspartyl protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
Biological sourceHomo sapiens (human)
Cellular locationMembrane; Single-pass type I membrane protein: P56817
Total number of polymer chains1
Total formula weight45900.71
Authors
Vigers, G.P.A.,Smith, D. (deposition date: 2013-03-18, release date: 2013-04-10, Last modification date: 2023-09-20)
Primary citationHunt, K.W.,Cook, A.W.,Watts, R.J.,Clark, C.T.,Vigers, G.,Smith, D.,Metcalf, A.T.,Gunawardana, I.W.,Burkard, M.,Cox, A.A.,Geck Do, M.K.,Dutcher, D.,Thomas, A.A.,Rana, S.,Kallan, N.C.,DeLisle, R.K.,Rizzi, J.P.,Regal, K.,Sammond, D.,Groneberg, R.,Siu, M.,Purkey, H.,Lyssikatos, J.P.,Marlow, A.,Liu, X.,Tang, T.P.
Spirocyclic beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: from hit to lowering of cerebrospinal fluid (CSF) amyloid beta in a higher species.
J.Med.Chem., 56:3379-3403, 2013
Cited by
PubMed Abstract: A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (Aβ), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Aβ is produced by the sequential cleavage of APP by BACE1 and γ-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Aβ in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Aβ lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Aβ in rodents and in monkey.
PubMed: 23537249
DOI: 10.1021/jm4002154
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.8 Å)
Structure validation

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