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

  • J Med Chem. 2020 Jan 9;63(1):425-432. doi: 10.1021/acs.jmedchem.9b01230.
Ina Lunk  1 ,  Felix-Alexander Litty  1 ,  Sven Hennig  2 ,  Ingrid R Vetter  3 ,  Jürke Kotthaus  1 ,  Karin S Altmann  1 ,  Gudrun Ott  1 ,  Antje Havemeyer  1 ,  Carmen Carrillo García  1 ,  Bernd Clement  1 ,  Dennis Schade  1  3  4
Affiliations
  • 1. Department of Pharmaceutical and Medicinal Chemistry , Christian-Albrechts-University Kiel , Gutenbergstrasse 76 , D-24118 Kiel , Germany.
  • 2. Department of Chemistry & Pharmaceutical Sciences , VU University Amsterdam , De Boelelaan 1108 , The Netherlands.
  • 3. Max-Planck-Institute of Molecular Physiology , Otto-Hahn-Strasse 11 , D-44227 Dortmund , Germany.
  • 4. Partner Site Kiel , DZHK, German Center for Cardiovascular Research , D-24105 Kiel , Germany.
PMID: 31841335 DOI: 10.1021/acs.jmedchem.9b01230
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.

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