JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate.

Autor:	Rombouts FJR; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., Kusakabe KI; Shionogi Pharmaceutical Research Center, Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Alexander R; Janssen Research & Development, Welsh & McKean Roads, Spring House, Pennsylvania 19477, United States., Austin N; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., Borghys H; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., De Cleyn M; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., Dhuyvetter D; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., Gijsen HJM; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., Hrupka B; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., Jacobs T; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., Jerhaoui S; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., Lammens L; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., Leclercq L; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., Tsubone K; Shionogi Pharmaceutical Research Center, Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Ueno T; Shionogi Pharmaceutical Research Center, Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Morimoto K; Shionogi Pharmaceutical Research Center, Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Einaru S; Shionogi Pharmaceutical Research Center, Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Sumiyoshi H; Shionogi Pharmaceutical Research Center, Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Van den Bergh A; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., Vos A; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., Surkyn M; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., Teisman A; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium., Moechars D; Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, Beerse B-2340, Belgium.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Oct 14; Vol. 64 (19), pp. 14175-14191. Date of Electronic Publication: 2021 Sep 23.
DOI:	10.1021/acs.jmedchem.1c00935
Abstrakt:	The discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pK a 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 ( 12 ), which gave robust dose-dependent BACE1-mediated amyloid β lowering without showing BACE2-dependent hair depigmentation in preclinical models. We show that 12 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, 12 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.
Databáze:	MEDLINE
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