Soluble Guanylyl Cyclase Activators—Promising Therapeutic Option in the Pharmacotherapy of Heart Failure and Pulmonary Hypertension

Figure 1. Schematic representation of the potential for pharmacological interference with the NO/sGC/cGMP pathway [3,5,6,7]. Explanation of abbreviations: sGC—soluble form of guanylyl cyclase; mGC—membrane form of guanylyl cyclase; NO—nitric oxide; eNOS—nitric oxide synthase; ANP, BNP, CMP—natriuretic peptide A, B or C; GMP 3′-5′—guanosine monophosphate; GTP 3′-5′—guanosine triphosphate; cGMP cyclic 3′-5′—guanosine monophosphate; CNGCs—cyclic nucleotide gated channels; PKG—protein kinase G; PDE phosphodiesterase.

Figure 2. The molecular structure of the studied sCG compounds.

Figure 3. The bioavailability radar of the sCG activators/stimulators. The gray area represents the optimal range for each of the properties (lipophilicity: XLOGP3 between −0.7 and +5.0, size: MW between 150 and 500 g/mol, polarity: TPSA between 20 and 130 Å2, solubility: log S no higher than 6, saturation: fraction of carbons in the sp3 hybridization no less than 0.25, and flexibility: no more than 9 rotatable bonds). The compounds names are indicated in the different font colors, i.e., black corresponds to sGC stimulators and orange corresponds to sGC activators.

Figure 4. The Brain Or IntestinaL EstimatED (BOILED-Egg) graph compared sGC and selected commonly use drugs. The colored areas represent the optimal prediction range (above 93%) of penetration for brain (BBB, yellow) and gastrointestinal tract (HIA, white). The gray color indicates the area where penetration into the brain and gastrointestinal tract may occur but its probability is below the optimal value. The molecule predicted to be evaluated from the central nervous system by the P-glycoprotein (blue dots) or not (red dots). The compounds names are indicated in the different font colors, i.e., black corresponds to sGC stimulators, orange corresponds to sGC activators, and purple corresponds to selected drugs.