Olinciguat, an Oral sGC Stimulator, Exhibits Diverse Pharmacology Across Preclinical Models of Cardiovascular, Metabolic, Renal, and Inflammatory Disease

Frontiers in Pharmacology (2020)

Daniel P. Zimmer, Courtney M. Shea, Jenny V. Tobin, Boris Tchernychev, Peter Germano, Kristie Sykes, Ali R. Banijamali, Sarah Jacobson, Sylvie G. Bernier, Renee Sarno, Andrew Carvalho, Yueh-tyng Chien, Regina Graul, Emmanuel S. Buys, Juli E. Jones, James D. Wakefield, Gavrielle M. Price, Jennifer G. Chickering, G. Todd Milne, Mark G. Currie and Jaime L. Masferrer

This research describes the potential clinical utility of olinciguat, based on studies investigating its pharmacokinetics, tissue distribution, and pharmacologic effects in preclinical models. In nonclinical models, olinciguat relaxed human vascular smooth muscle cells and was a potent inhibitor of vascular smooth muscle proliferation in vitro and lowered blood pressure in vivo. In preclinical animal models of disease, olinciguat was cardioprotective in the Dahl rat salt-sensitive hypertensive heart failure model. In the rat ZSF1 model of diabetic nephropathy and metabolic syndrome, olinciguat was renoprotective and associated with lower circulating glucose, cholesterol, and triglycerides. In a mouse TNFα-induced inflammation model, olinciguat treatment was associated with lower levels of endothelial and leukocyte-derived soluble adhesion molecules.

Effect of olinciguat on plasma levels of cellular adhesion molecules in mouse TNFα model of vascular inflammation. *p < 0.05, **p < 0.01, ****p < 0.0001 vs TNFα/vehicle control.


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