4B78

Aminoimidazoles as BACE-1 Inhibitors: From De Novo Design to Ab- lowering in Brain

Summary for 4B78

• Entry DOI: 10.2210/pdb4b78/pdb
• Related: 1FKN 1M4H 1PY1 1SGZ 1TQF 1UJJ 1UJK 1W50 1W51 1XN2 1XN3 1XS7 1YM2 1YM4 2B8L 2B8V 2FDP 2VA5 2VA6 2VA7 2VIE 2VIJ 2VIY 2VIZ 2VJ6 2VJ7 2VJ9 2VKM 2VNM 2VNN 2WEZ 2WF0 2WF1 2WF2 2WF3 2WF4 2WJO 2XFI 2XFJ 2XFK 4ACU 4ACX 4AZY 4B00 4B05 4B0Q 4B1C 4B1D 4B1E 4B70 4B72 4B77
• Descriptor: BETA-SECRETASE 1, (3R,5R)-3-methoxy-5-(4-methoxyphenyl)-5-(3-pyridin-3-ylphenyl)-3,4-dihydropyrrol-2-amine (3 entities in total)
• Functional Keywords: hydrolase, hydrolase inhibitor, lead generation, structure-based drug design
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 1
• Total formula weight: 43181.72

Authors

Gravenfors, Y.,Blid, J.,Ginman, T.,Karlstrom, S.,Kihlstrom, J.,Kolmodin, K.,Lindstrom, J.,Berg, S.,Kieseritzky, F.,Slivo, C.,Swahn, B.,Viklund, J.,Olsson, L.,Johansson, P.,Eketjall, S.,Falting, J.,Jeppsson, F.,Stromberg, K.,Janson, J.,Rahm, F. (deposition date: 2012-08-16, release date: 2013-06-26, Last modification date: 2013-07-03)

Primary citation

Ginman, T.,Viklund, J.,Malmstrom, J.,Blid, J.,Emond, R.,Forsblom, R.,Johansson, A.,Kers, A.,Lake, F.,Sehgelmeble, F.,Sterky, K.J.,Bergh, M.,Lindgren, A.,Johansson, P.,Jeppsson, F.,Falting, J.,Gravenfors, Y.,Rahm, F.
Core Refinement Toward Permeable Beta-Secretase (Bace-1) Inhibitors with Low Herg Activity.
J.Med.Chem., 56:4181-, 2013

PubMed Abstract: By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure-activity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 μM to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds.

PubMed: 23126626
DOI: 10.1021/JM3011349

Experimental method

X-RAY DIFFRACTION (1.5 Å)