Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension

Mittendorf, Joachim; Weigand, Stefan; Alonso‐Alija, Cristina; Bischoff, Erwin; Feurer, Achim; Gerisch, Michael; Kern, Armin; Knorr, Andreas; Lang, Dieter; Muenter, Klaus; Radtke, Martin; Schirok, Hartmut; Schlemmer, Karl‐Heinz; Stahl, Elke; Straub, Alexander; Wunder, Frank; Stasch, Johannes‐Peter

doi:10.1186/1471-2210-9-s1-p52

Cited by 43 publications

(59 citation statements)

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“…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).…”

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

Nakai

Perl

Barden

et al. 2016

ACS Med. Chem. Lett.

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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...

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confidence: 99%

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

Nakai

Perl

Barden

et al. 2016

ACS Med. Chem. Lett.

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“…The diatomic messenger NO and sGC play a critical role in several physiological processes: regulation of vascular blood pressure and cardiovascular diseases (3), lung airway relaxation and pulmonary pathologies (4), immune response and inflammatory disorders (5), and tumor progression and apoptosis (6). Thus, sGC is a pharmacological target of very high interest, and several activators have been developed (7,8), leading to the approval of riociguat for the treatment of pulmonary hypertension (9,10). Because of its pharmacological interest, the mechanisms of activation, deactivation, and regulation of sGC must be deciphered at the molecular level.…”

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confidence: 99%

Motion of proximal histidine and structural allosteric transition in soluble guanylate cyclase

Yoo

Lamarre

Martin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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We investigated the changes of heme coordination in purified soluble guanylate cyclase (sGC) by time-resolved spectroscopy in a time range encompassing 11 orders of magnitude (from 1 ps to 0.2 s). After dissociation, NO either recombines geminately to the 4-coordinate (4c) heme (τ G1 = 7.5 ps; 97 ± 1% of the population) or exits the heme pocket (3 ± 1%). The proximal His rebinds to the 4c heme with a 70-ps time constant. Then, NO is distributed in two approximately equal populations (1.5%). One geminately rebinds to the 5c heme (τ G2 = 6.5 ns), whereas the other diffuses out to the solution, from where it rebinds bimolecularly (τ = 50 μs with [NO] = 200 μM) forming a 6c heme with a diffusion-limited rate constant of 2 × 10 8 M −1 ·s −1 . In both cases, the rebinding of NO induces the cleavage of the Fe-His bond that can be observed as an individual reaction step. Saliently, the time constant of bond cleavage differs depending on whether NO binds geminately or from solution (τ 5C1 = 0.66 μs and τ 5C2 = 10 ms, respectively). Because the same event occurs with rates separated by four orders of magnitude, this measurement implies that sGC is in different structural states in both cases, having different strain exerted on the Fe-His bond. We show here that this structural allosteric transition takes place in the range 1-50 μs. In this context, the detection of NO binding to the proximal side of sGC heme is discussed.soluble guanylate cyclase | nitric oxide | time-resolved absorption spectroscopy | allostery | protein activation T he soluble guanylate cyclase (sGC), localized in many different cell types, is the receptor of the endogenous messenger nitric oxide (NO) and catalyzes the formation of cGMP from GTP upon activation triggered by NO binding (1, 2). The diatomic messenger NO and sGC play a critical role in several physiological processes: regulation of vascular blood pressure and cardiovascular diseases (3), lung airway relaxation and pulmonary pathologies (4), immune response and inflammatory disorders (5), and tumor progression and apoptosis (6). Thus, sGC is a pharmacological target of very high interest, and several activators have been developed (7,8), leading to the approval of riociguat for the treatment of pulmonary hypertension (9, 10). Because of its pharmacological interest, the mechanisms of activation, deactivation, and regulation of sGC must be deciphered at the molecular level. Despite numerous efforts, the 3D crystal structure of heterodimeric sGC remains unknown, but the heme domain of the sGC β1-subunit [called heme NO/oxygen-binding (H-NOX)] was modeled from the heme domain of bacterial NO sensors (11,12) and the sGC catalytic α1-subunit was modeled from the catalytic α1-subunit of adenylate cyclase (13). Recently, the entire quaternary structure of sGC was reconstructed by inserting individual protein domains into the density envelope of entire single-sGC molecules observed by EM (14), revealing a high flexibility of the sGC dimer. Subsequently, the structural perturbations induced by NO bi...

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“…In PH, production of NO is reduced, resulting in inhibition of sGC activity and depletion of cGMP which can lead to numerous abnormalities including pulmonary vasoconstriction, adverse vascular remodelling and in situ thrombosis [21,22]. Riociguat is the first of a new class of drugs, the sGC stimulators, designed to both stimulate sGC independently of NO and sensitise the enzyme to low levels of NO, thereby restoring cGMP levels [23]. As a result of its NO-independent action, riociguat could be effective under conditions of NO depletion that restrict the effectiveness of PDE-5 inhibitors.…”

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Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial

et al. 2012

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We assessed the safety, tolerability and preliminary efficacy of riociguat, a soluble guanylate cyclase stimulator, in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD).In this open-label, uncontrolled pilot trial, patients received oral riociguat (1.0-2.5 mg three times daily) for 12 weeks (n522), followed by an ongoing long-term extension (interim analysis at 12 months) in those eligible (n515). Primary end-points were safety and tolerability. Secondary end-points included haemodynamic changes and 6-min walk distance (6MWD).Overall, 104 adverse events were reported, of which 25 were serious; eight of the latter were considered drug-related. After 12 weeks of therapy, mean cardiac output increased (4.4¡1.5 L?min ) and mean pulmonary artery pressure (mPAP) remained unchanged compared with baseline. Arterial oxygen saturation decreased but mixed-venous oxygen saturation slightly increased. The 6MWD increased from 325¡96 m at baseline to 351¡111 m after 12 weeks.Riociguat was well tolerated by most patients and improved cardiac output and PVR, but not mPAP. Further studies are necessary to evaluate the safety and efficacy of riociguat in patients with PH-ILD.

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Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension

Cited by 43 publications

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

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

Motion of proximal histidine and structural allosteric transition in soluble guanylate cyclase

Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial

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