Discovery of the Soluble Guanylate Cyclase Activator Runcaciguat (BAY 1101042)

Herein we describe
the discovery, mode of action, and preclinical
characterization of the soluble guanylate cyclase (sGC) activator
runcaciguat. The sGC enzyme, via the formation of cyclic guanosine
monophoshphate, is a key regulator of body and tissue homeostasis.
sGC activators with their unique mode of action are activating the
oxidized and heme-free and therefore NO-unresponsive form of sGC,
which is formed under oxidative stress. The first generation of sGC
activators like cinaciguat or ataciguat exhibited limitations and
were discontinued. We overcame limitations of first-generation sGC
activators and identified a new chemical class via high-throughput
screening. The investigation of the structure–activity relationship
allowed to improve potency and multiple solubility, permeability,
metabolism, and drug-drug interactions parameters. This program resulted
in the discovery of the oral sGC activator runcaciguat (compound 45, BAY 1101042). Runcaciguat is currently investigated in
clinical phase 2 studies for the treatment of patients with chronic
kidney disease and nonproliferative diabetic retinopathy.