Selective substrate-based inhibitors of mammalian dimethylarginine dimethylaminohydrolase.
The enzyme DDAH metabolizes methylarginines that are inhibitors of nitric oxide synthase (NOS). Substrate-based inhibitors of mammalian DDAH have been synthesized, with optimization to give selective inhibition of DDAH with no significant direct effect on NOSs. These are the first examples of reversible DDAH inhibitors with significant activity and selectivity. In vivo administration increases plasma ADMA levels, giving proof of concept that these inhibitors can be used to probe the physiological effects of DDAH inhibition, with potential for pharmaceutical use of DDAH inhibitors in diseases where excess NO production is implicated.
Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, BHF Laboratories, Rayne Building, University College London, UK. s.rossiter@ucl.ac.uk
Sharon
S
Rossiter
Caroline L
CL
Smith
Mohammed
M
Malaki
Manasi
M
Nandi
Herpreet
H
Gill
James M
JM
Leiper
Patrick
P
Vallance
David L
DL
Selwood
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D011921:Rats, Inbred WKY; D013329:Structure-Activity Relationship
C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000581:Amidohydrolases; C059999:dimethylargininase