BAY 41-2272

Description

Soluble guanylate cyclase (sGC), a receptor for nitric oxide (NO), is a heterodimer consisting of alpha and beta subunits, with the beta subunit featuring a heme-nitric oxide (H-NOX) binding domain. The binding of NO to H-NOX induces sGC to generate the second messenger cGMP. BAY 41-2272 is a pyrazolopyridine compound that acts as an activator of sGC, stimulating activity to a level that would be expected to cause biologically important increases in cGMP at concentrations as low as 10-100 nM. Through this effect, it inhibits platelet aggregation (IC₅₀ = 36 nM), induces relaxation of phenylephrine-preconstricted rabbit aorta rings (IC₅₀ = 304 nM), and reduces proliferation in smooth muscle. BAY 41-2272 is effective in vivo, as it decreases mean arterial blood pressure in hypertensive rats. Unlike another sGC activator, YC-1 , BAY 41-2772 does not inhibit phosphodiesterases.

Uses

BAY 41-2272 is a soluble guanylate cyclase agonist that activates human mononuclear phagocytes. Inhibits vascular smooth muscle growth through the cAMP-dependent protein kinase and cGMP-dependent protein kinase pathways.

Definition

ChEBI: BAY 41-2272 is a pyrazolopyridine that is 1H-pyrazolo[3,4-b]pyridine which is substituted by a 2-fluorobenzyl group at position 1 and by a 4-amino-5-cyclopropylpyrimidin-2-yl group at position 3. It is an activator of soluble guanylate cyclase. It has a role as a soluble guanylate cyclase activator, a platelet aggregation inhibitor, a vasodilator agent and an antihypertensive agent. It is a pyrazolopyridine, a member of monofluorobenzenes, an aminopyrimidine and a member of cyclopropanes.

General Description

A cell-permeable pyrazolopyridinylpyrimidine compound that acts as a selective and potent stimulator of soluble guanylate cyclase (effective dose ~ 0.1 nM to 100 μM using recombinant soluble guanylate cyclase). The mode of activation is NO-independent and appears to be mediated through direct binding to the α₁ and α₂ subunits. Shown to be effective in treating numerous cardiovascular conditions in animal models. Inhibits phenylephrine-induced constriction of rabbit aortic rings (IC₅₀ = 304 nM) and blocks collagen-induced aggregation of human platelets (IC₅₀ = 36 nM). Does not inhibit phosphodiesterases.

Biochem/physiol Actions

Cell permeable: yes

Synthesis

The general procedure for the synthesis of 5-cyclopropyl-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-amine from 2-cyclopropyl-3-oxopropanenitrile and 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-amine was as follows: 103.7 mg (0.38 mmol) of 1-(2-fluorobenzyl )-1H-pyrazolo[3,4-B]pyridine-3-carboxamidine and 168.1 mg (1.54 mmol) of crude 2-cyclopropyl-3-oxopropanenitrile were dissolved in 0.5 ml of toluene and mixed thoroughly in an ultrasonic bath. Subsequently, the toluene was evaporated under reduced pressure, and the mixture was transferred to an open vessel and heated to 100-105 °C for 1 h under solvent-free conditions for the reaction. Upon completion of the reaction, the mixture was cooled to room temperature and the residue was dissolved in dichloromethane and mixed with 1 g of silica gel, followed by concentration of the mixture using a rotary evaporator. To purify the product, the separation was carried out by column chromatography on silica gel 60 (particle size 0.040-0.063 mm) with cyclohexane/ethyl acetate (1:1) as mobile phase. The final product was obtained as 50.0 mg with a yield of 36.0% of the theoretical value. Thin layer chromatography (TLC) analysis showed an Rf value of 0.23 (SiO2, ethyl acetate/cyclohexane).

storage

Store at +4°C

References

[1] Patent: US6833364, 2004, B1. Location in patent: Page column 37,38
[2] Patent: US6833364, 2004, B1. Location in patent: Page column 37