7N66
BACE-1 in complex with ligand 12
Summary for 7N66
| Entry DOI | 10.2210/pdb7n66/pdb |
| Descriptor | Beta-secretase 1, IODIDE ION, GLYCEROL, ... (6 entities in total) |
| Functional Keywords | bace protease, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 47884.55 |
| Authors | Shaffer, P.L. (deposition date: 2021-06-07, release date: 2021-10-06, Last modification date: 2024-10-16) |
| Primary citation | Rombouts, F.J.R.,Kusakabe, K.I.,Alexander, R.,Austin, N.,Borghys, H.,De Cleyn, M.,Dhuyvetter, D.,Gijsen, H.J.M.,Hrupka, B.,Jacobs, T.,Jerhaoui, S.,Lammens, L.,Leclercq, L.,Tsubone, K.,Ueno, T.,Morimoto, K.,Einaru, S.,Sumiyoshi, H.,Van den Bergh, A.,Vos, A.,Surkyn, M.,Teisman, A.,Moechars, D. JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate. J.Med.Chem., 64:14175-14191, 2021 Cited by PubMed Abstract: The discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pK and lipophilicity were modulated by a pending sulfonyl group, while good permeability and brain penetration were achieved via intramolecular hydrogen bonding. BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel bicyclic ring system. An optimization addressing reactive metabolite formation, cardiovascular safety, and CNS toxicity is described, leading to the clinical candidate JNJ-67569762 (), which gave robust dose-dependent BACE1-mediated amyloid β lowering without showing BACE2-dependent hair depigmentation in preclinical models. We show that has a favorable projected human dose and PK and hence presented us with an opportunity to test a highly selective BACE1 inhibitor in humans. However, was found to have a QT effect upon repeat dosing in dogs and its development was halted in favor of other selective leads, which will be reported in the future. PubMed: 34553934DOI: 10.1021/acs.jmedchem.1c00935 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
Download full validation report
