Heme-dependent Activators of Soluble Guanylyl/Guanylate Cyclase

YC-1

[3-(5'-Hydroxymethyl-2'-furyl)-1-benzylindazole]

Potency: -

Membrane permeability: Y / Solubility: DMSO / MW: 304.3

Comments: It stimulate soluble guanylyl cyclase by the sensitization of the enzyme to NO. This effect is supposed to be mediated by inhibition of its deactivation, probably by inhibition of NO dissociation from the prosthetic haem group of the enzyme. More information about the use of this drug can be found in references 1, 2 and 3.

¹Ko FN, Wu CC, Kuo SC, Lee FY, Teng CM. YC-1, a novel activator of platelet guanylate cyclase. Blood 1994;84:4226.

²Friebe A, Koesling D. Mechanism of YC-1-Induced Activation of Soluble Guanylyl Cyclase. Mol Pharmacol 1998;53:123.

³Martin E, Lee YC, Murad F. YC-1 activation of human soluble guanylyl cyclase has both heme-dependent and heme-independent components. Proc Natl Acad Sci USA 2001;98:12938.

CAUTION: It has been described to inhibit phosphodiesterase 5 (PDE5). Notes: It could also inhibit other phosphodiesterase isozymes. It has been suggested that some of the YC-1 effects observed in intact cells may be caused by the inhibition of phosphodiesterases rather than solely by the stimulation of NO-sensitive guanylyl cyclase.

BAY 41-2272

[3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine]

Potency: IC₅₀= 304 nM (inhibition of phenylephrine-induced constriction of rabbit aortic rings), 36 nM (inhibition of collagen-induced aggregation of human platelets)¹; EC₅₀= 0.3 µmol/L - 3 µmol/L with/without DEA-NO 100 nmol/L.

Membrane permeability: Y / Solubility: DMSO / MW: 360.40

Comments: It can be obtained from standard distributors or donated by the company. It evokes by its own a 30% of activation of the NO-sensitive guanylyl cyclase, and increase a 20% the maximal stimulatory effect of NO. A mechanism of action similar to YC-1 is supposed (sensitization of NO-sensitive guanylyl cyclase by inhibition of its deactivation, probably by inhibition of NO dissociation from the prosthetic haem group of the enzyme).

¹Inhibitor SourceBook, Calbiochem, Merck Biosciences

CAUTION: It has been described to inhibit phosphodiesterase 5 (PDE5)¹.

¹Mullershausen F, Russwurm M, Friebe A, Koesling D. Inhibition of phosphodiesterase type 5 by the activator of nitric oxide-sensitive guanylyl cyclase BAY 41-2272. Circulation 2004;109:1711.