2. Academic Validation
  3. 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)

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

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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