NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential.
Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impaired bioavailability and/or responsiveness to endogenous NO has been implicated in the pathogenesis of cardiovascular and other diseases. Current therapies that involve the use of organic nitrates and other NO donors have limitations, including non-specific interactions of NO with various biomolecules, lack of response and the development of tolerance following prolonged administration. Compounds that activate sGC in an NO-independent manner might therefore provide considerable therapeutic advantages. Here we review the discovery, biochemistry, pharmacology and clinical potential of haem-dependent sGC stimulators (including YC-1, BAY 41-2272, BAY 41-8543, CFM-1571 and A-350619) and haem-independent sGC activators (including BAY 58-2667 and HMR-1766).
Evgenov
Oleg V
OV
Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, CLN 309, Boston, Massachusetts 02114, USA.
Pacher
Pál
P
Schmidt
Peter M
PM
Haskó
György
G
Schmidt
Harald H H W
HH
Stasch
Johannes-Peter
JP
D000818:Animals; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism*
D020536:Enzyme Activators; D009569:Nitric Oxide; D006162:Guanylate Cyclase