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: Soluble guanylate cyclase, sGC, NO-independent stimulators, heme-dependent sGC stimulators, nitric oxide, IWP-051 S oluble guanylate cyclase (sGC, EC 4.6.1.2) is a signaltransduction enzyme that binds nitric oxide (NO) and catalyzes the conversion of guanosine-5′-triphosphate (GTP) to the secondary messenger cyclic guanosine-3′,5′-monophosphate (cGMP). The NO-sGC-cGMP signal-transduction pathway is involved in the regulation of various physiological processes, including smooth muscle relaxation, platelet inhibition, and vasodilation. 1 The NO-sGC-cGMP pathway plays an important role in coordinating blood flow to tissues, providing oxygen and nutrients, and removing waste products in response to local demands. 2 Impairment of sGC and/or reduced NO bioavailability has been implicated in the pathogenesis of cardiovascular, pulmonary, renal, and hepatic diseases. 3 The therapeutic benefit of NO-donors such as organic nitrates is limited by lack of efficacy due to variable biometabolism 4 and the development of NO tolerance. 5 An alternative to NO-donors are sGC stimulators, a class of ligands that bind allosterically to the Fe(II) form of the hemecontaining enzyme and stimulate the formation of cGMP. 6,7 sGC stimulators can act both independently and in synergy with NO. In preclinical models, sGC stimulators have demonstrated anti-inflammatory and antifibrotic effects, as well as end-organ protections. 8−11 The first marketed sGC stimulator, Bayer's riociguat (Adempas) (Figure 1), was approved in 2013 by the FDA for the treatment of pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH) based on its ability to improve exercise capacity and symptomatic profile with disease severity defined by the World Health Organization functional classification system. 12 We sought to design an sGC stimulator with a sustained pharmacokinetic and pharmacodynamic profile allowing once-daily dosing and potential to minimize the risk of hypotensive side effects.Some known sGC stimulators, such as riociguat and BAY 41-2272, 13 feature a fused ring structure (Figure 1). We have focused our discovery effort on sGC stimulators that utilize a novel, biaryl pyrazole structure, as exemplified by 1 14 ( Figure 1). 1 is a potent sGC stimulator as determined by production of cGMP in a human embryonic kidney (HEK) cellular assay in the presence of the NO-donor diethylenetriamine NONO...

Discovery of stimulator binding to a conserved pocket in the heme domain of soluble guanylyl cyclase

“…Second, there is a weak TrNOESY peak between an isoxazole proton and the methylene protons (H10-H11, Fig. 4B), consistent with the orientation shown in the figure and the previously reported structure-activity relationship (SAR) of IWP-051 (11). Third, the appearance of several TrNOESY peaks for the benzyl ring indicates it occupies a single conformation in the binding pocket.…”

“…The IWP-854 core motif is based on IWP-051, which replaces the 7-azaindazole core of BAY 41-2272 with pyrazole-isoxazole 5-membered rings capable of free rotation (Fig. 1B) (11). Previous studies indicate altering the benzyl ring abolishes binding while modifications to the pyrimidine ring are widely tolerated (11,12).…”

“…1B) (11). Previous studies indicate altering the benzyl ring abolishes binding while modifications to the pyrimidine ring are widely tolerated (11,12). With this in mind, we modified the pyrimidine ring to have a biotin affinity tag coupled to a PEG linker and a photoactive diazirine capable of covalently attaching to all 20 amino acid side chains and peptide backbone (13)(14)(15) (Fig.…”

“…1B). The pyrimidine ring was previously shown to be tolerant to some modification (11), suggesting it may exhibit greater conformational dynamics than the rest of the compound, even in the bound state.…”

“…Optimization of initial stimulator compounds led to the development of BAY 41-2272, which is widely used for investigating stimulator mechanism, and BAY 63-2521 (riociguat), which is clinically approved to treat pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) (marketed as Adempas) (3). Additional sGC stimulators have been developed, including IWP-051, a novel compound representing a new class of stimulators with improved solubility over traditional stimulators and favorable pharmacodynamics properties (11).…”