Discovery of N-(4-Aminobutyl)-N'-(2-methoxyethyl)guanidine as the First Selective, Nonamino Acid, Catalytic Site Inhibitor of Human Dimethylarginine Dimethylaminohydrolase-1 (hDDAH-1)

Ina Lunk, Felix-Alexander Litty, Sven Hennig, Ingrid R Vetter, Jürke Kotthaus, Karin S Altmann, Gudrun Ott, Antje Havemeyer, Carmen Carillo García, Bernd Clement, Dennis Schade

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

N-(4-Aminobutyl)-N′-(2-methoxyethyl)guanidine (8a) is a potent inhibitor targeting the hDDAH-1 active site (Ki = 18 μM) and derived from a series of guanidine- and amidine-based inhibitors. Its nonamino acid nature leads to high selectivities toward other enzymes of the nitric oxide-modulating system. Crystallographic data of 8a-bound hDDAH-1 illuminated a unique binding mode. Together with its developed N-hydroxyguanidine prodrug 11, 8a will serve as a most widely applicable, pharmacological tool to target DDAH-1-associated diseases.

Original languageEnglish
Pages (from-to)425-432
Number of pages8
JournalJournal of Medicinal Chemistry
Volume63
Issue number1
Early online date16 Dec 2019
DOIs
Publication statusPublished - 9 Jan 2020

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