Mitigating the Metabolic Liability of Carbonyl Reduction: Novel Calpain Inhibitors with P1' Extension.

Autor:	Kling A; Neuroscience Research, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany., Jantos K; Neuroscience Research, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany., Mack H; Neuroscience Research, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany., Hornberger W; Neuroscience Research, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany., Backfisch G; Development Sciences, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany., Lao Y; AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064-6125, United States., Nijsen M; AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064-6125, United States., Rendenbach-Mueller B; Neuroscience Development, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany., Moeller A; Neuroscience Research, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2018 Feb 04; Vol. 9 (3), pp. 221-226. Date of Electronic Publication: 2018 Feb 04 (Print Publication: 2018).
DOI:	10.1021/acsmedchemlett.7b00494
Abstrakt:	Dysregulation of calpains 1 and 2 has been implicated in a variety of pathological disorders including ischemia/reperfusion injuries, kidney diseases, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). 2-(3-Phenyl-1 H )-pyrazol-1-yl)nicotinamides represent a series of novel and potent calpain inhibitors with high selectivity and in vivo efficacy. However, carbonyl reduction leading to the formation of the inactive hydroxyamide was identified as major metabolic liability in monkey and human, a pathway not reflected by routine absorption, distribution, metabolism, and excretion (ADME) assays. Using cytosolic clearance as a tailored in vitro ADME assay coupled with in vitro hepatocyte metabolism enabled the identification of analogues with enhanced stability against carbonyl reduction. These efforts led to the identification of P1' modified calpain inhibitors with significantly improved pharmacokinetic profile including P1' N -methoxyamide 23 as potential candidate compound for non-central nervous system indications. Competing Interests: The authors declare the following competing financial interest(s): The authors are current or former employees of AbbVie (or Abbott Laboratories prior to separation), and may own company stock.
Databáze:	MEDLINE
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