4FSL

Crystal structure of beta-site app-cleaving enzyme 1 (BACE-DB-MUT) complex with N-(N-(4- acetamido-3-chloro-5-methylbenzyl)carbamimidoyl)-3-(4- methoxyphenyl)-5-methyl-4-isothiazolecarboxamide

Summary for 4FSL

• Entry DOI: 10.2210/pdb4fsl/pdb
• Related: 4FSE
• Descriptor: Beta-secretase 1, N-{N-[4-(acetylamino)-3-chloro-5-methylbenzyl]carbamimidoyl}-3-(4-methoxyphenyl)-5-methyl-1,2-thiazole-4-carboxamide, IODIDE ION, ... (4 entities in total)
• Functional Keywords: alzheimer's disease, beta-secretase, memapsin 2, base, aspartic protease, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 187160.98

Authors

Muckelbauer, J.K. (deposition date: 2012-06-27, release date: 2012-10-10, Last modification date: 2024-10-16)

Primary citation

Gerritz, S.W.,Zhai, W.,Shi, S.,Zhu, S.,Toyn, J.H.,Meredith, J.E.,Iben, L.G.,Burton, C.R.,Albright, C.F.,Good, A.C.,Tebben, A.J.,Muckelbauer, J.K.,Camac, D.M.,Metzler, W.,Cook, L.S.,Padmanabha, R.,Lentz, K.A.,Sofia, M.J.,Poss, M.A.,Macor, J.E.,Thompson, L.A.
Acyl Guanidine Inhibitors of beta-Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution-Phase Library Synthesis
J.Med.Chem., 55:9208-9223, 2012

PubMed Abstract: This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-π interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma Aβ levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain Aβ levels were not obtained.

PubMed: 23030502
DOI: 10.1021/jm300931y

Experimental method

X-RAY DIFFRACTION (2.5 Å)