Discovery of IWP-051, a Novel Orally Bioavailable sGC Stimulator with Once-Daily Dosing Potential in Humans

Abstract

In recent years, soluble guanylate cyclase (sGC, EC 4.6.1.2) has emerged as an attractive therapeutic target for treating cardiovascular diseases and diseases associated with fibrosis and end-organ failure. Herein, we describe our design and synthesis of a series of 4-hydroxypyrimidine sGC stimulators starting with an internally discovered lead. Our efforts have led to the discovery of IWP-051, a molecule that achieves good alignment of potency, stability, selectivity, and pharmacodynamic effects while maintaining favorable pharmacokinetic properties with once-daily dosing potential in humans.

Keywords: IWP-051; NO-independent stimulators; Soluble guanylate cyclase; heme-dependent sGC stimulators; nitric oxide; sGC.

Figure 1

Three examples of sGC stimulators.

Scheme 1. Synthesis of Analogs 4 and 5

Scheme 2. General Synthesis of Pyrimidine Analogs

Figure 2

IWP-051 (1, 10, and 30 mg/kg in PEG400) and Bay 41-2272 (10 mg/kg in 0.5% methylcelluolose, Sigma-Aldrich) were dosed orally to male, normotensive Sprague–Dawley rats. Vehicle-subtracted mean arterial pressure (Δ_vMAP) in mmHg was monitored for 12–24 h via a conscious, tethered rat model. Data is represented as the change from their own vehicles as 1 h averages + SEM, n = 5–9.