NO-independent regulatory site on soluble guanylate cyclase.
Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pathophysiological roles. Research in the field of NO appears to have followed a straightforward path, and the findings have been progressive: NO and cyclic GMP are involved in vasodilatation; glycerol trinitrate relaxes vascular smooth muscles by bioconversion to NO; mammalian cells synthesize NO; and last, NO mediates vasodilatation by stimulating the soluble guanylate cyclase (sGC), a heterodimeric (alpha/beta) haem protein that converts GTP to cGMP2-4. Here we report the discovery of a regulatory site on sGC. Using photoaffinity labelling, we have identified the cysteine 238 and cysteine 243 region in the alpha1-subunit of sGC as the target for a new type of sGC stimulator. Moreover, we present a pyrazolopyridine, BAY 41-2272, that potently stimulates sGC through this site by a mechanism that is independent of NO. This results in antiplatelet activity, a strong decrease in blood pressure and an increase in survival in a low-NO rat model of hypertension, and as such may offer an approach for treating cardiovascular diseases.
Pharma Research Center, Bayer AG, Aprather Wey 18a, D-42096 Wuppertal, Germany. johannes-peter.stasch.js@bayer-ag.de
J P
JP
Stasch
E M
EM
Becker
C
C
Alonso-Alija
H
H
Apeler
K
K
Dembowsky
A
A
Feurer
R
R
Gerzer
T
T
Minuth
E
E
Perzborn
U
U
Pleiss
H
H
Schröder
W
W
Schroeder
E
E
Stahl
W
W
Steinke
A
A
Straub
M
M
Schramm
D000595:Amino Acid Sequence; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003545:Cysteine / Q000737:chemistry; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D006162:Guanylate Cyclase / Q000737:chemistry* / Q000378:metabolism; D006418:Heme / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000737:chemistry*; D019920:Photoaffinity Labels; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D012995:Solubility
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D000959:Antihypertensive Agents; D003497:Cyclic N-Oxides; D007093:Imidazoles; D007191:Indazoles; D019920:Photoaffinity Labels; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D009569:Nitric Oxide; D006418:Heme; D006162:Guanylate Cyclase; D003545:Cysteine