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)

Abstract

N-(4-Aminobutyl)-N′-(2-methoxyethyl)­guanidine (8a) is a potent inhibitor targeting the hDDAH-1 active site (K i = 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.

Recent advances in DDAH1 inhibitor design and discovery: insights from structure–activity relationships and X-ray crystal structures

“…However, butyl amine (50, K i = 59 mM) and amino pentanoic acid (51, K i = 57 mM) groups restored ligand activity. 28 Notably, arginine analog 46 (K i = 18 mM) gave comparable potency and selectivity to L-257 (13, K i = 13 mM, Fig. 5) over NOS and arginase.…”

“…However, major limitations of known DDAH1 inhibitors displaying non-specic interactions with NOS and arginase. 26,28,32 Also for most of the DDAH1 inhibitors (both arginine and non-arginine-like) limited information of their pharmacokinetic proles are available with only a few studies performed in animal models. Pharmacokinetic data is available for L-257 (13), ZST316 (20) and ZST152 (24) 40,41 and animal studies detailing the effects of DDAH1 inhibition of L-257 (ref.…”

“…Furthermore, it was proposed that the 2-methoxyethyl substituent of 13 is not favourable for binding to the NOS active site (possibly a consequence of inappropriate steric and/or electrostatic interactions) hence more selective for DDAH1. 23,26 Therefore, following from Kotthaus study, Lunk et al 28 investigated a diverse range of methoxy and alkenyl substitutions by shortening and extending the C side chain, leading to improved potency and selectivity towards hDDAH1. Major advancements from this study include the identication of a novel selective hDDAH1 inhibitor with a novel binding mode.…”

“…However, butyl amine ( 50 , K i = 59 μM) and amino pentanoic acid ( 51 , K i = 57 μM) groups restored ligand activity. 28…”

“…Comparison of these inhibitors bound to h DDAH1 (ref. 28) all show the α-amino group positioned tightly by H-bonds, interacting with the side chain of Asp73 and backbone carbonyl interactions of Leu30 and Val268. This highlights the importance of the α-amine group likely due to the optimal geometry of all H-bond partners.…”