4jpe | pdb_00004jpe
Spirocyclic Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors
Structural highlights
Function[BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2] Publication Abstract from PubMedA hallmark of Alzheimer's disease is the brain deposition of amyloid beta (Ass), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Ass is produced by the sequential cleavage of APP by BACE1 and gamma-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 Ass 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 Ass lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Ass in rodents and in monkey. Spirocyclic ss-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: From Hit to Lowering of Cerebrospinal Fluid (CSF) Amyloid Beta in a Higher Species.,Hunt KW, Cook AW, Watts RJ, Clark CT, Vigers G, Smith D, Metcalf AT, Gunawardana IW, Burkard M, Cox AA, Geck-Do M, Dutcher D, Thomas AA, Rana S, Kallan NC, Delisle RK, Rizzi JP, Regal K, Sammond D, Groneberg R, Siu M, Purkey H, Lyssikatos JP, Marlow A, Liu X, Tang TP J Med Chem. 2013 Mar 28. PMID:23537249[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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