Contemporary Accounts in Drug Discovery and Development. Группа авторов

J. Clin. Invest. 130: 1863–1878.

      122 122 BioSpace (2020). Nimbus Therapeutics announces $60 million private financing from new investors to advance expanded pipeline. https://www.biospace.com/article/nimbus‐therapeutics‐announces‐60‐million‐private‐financing‐from‐new‐investors‐to‐advance‐expanded‐pipeline (accessed 29 December 2020).

      123 123 Hammitzsch, A., Lorenz, G., and Moog, P. (2020). Impact of Janus kinase inhibition on the treatment of axial spondyloarthropathies. Front. Immunol. 11: 591176.

      124 124 Associated Press (2020).Nimbus Therapeutics announces $60 million private financing from new investors to advance expanded pipeline. https://apnews.com/press‐release/business‐wire/business‐corporate‐news‐massachusetts‐drug‐trials‐products‐and‐services‐e3c360003ea74eec9f626a3e82790b86 (accessed 29 December 2020).

      125 125 Mortier, J., Friberg, A., Badock, V. et al. (2020). Computationally empowered workflow identifies novel covalent allosteric binders for KRAS. ChemMedChem 15: 827–832.

      126 126 Conti, M. (2000). Phosphodiesterases and cyclic nucleotide signaling in endocrine cells. Mol. Endocrinol.: 1317–1327. https://doi.org/10.1210/mend.14.9.0534.

      127 127 Maurice, D.H., Ke, H., Ahmad, F. et al. (2014). Advances in targeting cyclic nucleotide phosphodiesterases. Nat. Rev. Drug Discov. 13: 290–314.

      128 128 Gomez, L. and Guy, B.J. (2013). PDE2 inhibition: potential for the treatment of cognitive disorders. Bioorg. Med. Chem. Lett.: 6522–6527. https://doi.org/10.1016/j.bmcl.2013.10.014.

      129 129 Wu, Y., Li, Z., Huang, Y.‐Y. et al. (2018). Novel phosphodiesterase inhibitors for cognitive improvement in Alzheimer's disease. J. Med. Chem. 61: 5467–5483.

      130 130 Tresadern, G., Velter, I., Trabanco, A.A. et al. (2020). [1,2,4]Triazolo[1,5‐]pyrimidine phosphodiesterase 2A inhibitors: structure and free‐energy perturbation‐guided exploration. J. Med. Chem. 63: 12887–12910.

3 Discovery and Development of the Soluble Guanylate Cyclase Stimulator Vericiguat for the Treatment of Chronic Heart Failure

       Markus Follmann, Corina Becker, Lothar Roessig, Peter Sandner, and Johannes‐Peter Stasch

       Research & Development, Pharmaceuticals, Bayer AG, Aprather Weg 18a, 42096, Wuppertal, Germany

3.1 Introduction

Despite better therapies, cardiovascular (CV) diseases remain the leading cause of death worldwide. Among them, heart failure (HF) is a leading cause of hospitalization and CV death [1]. More than 63 million people worldwide suffered from HF in 2016 [2], and around 50% of patients with HF die within five years [3]. HF, by definition, is a condition where the heart is unable to pump sufficiently in order to provide adequate blood flow to other organs such as the kidneys and the brain. Overall, it is a complex clinical syndrome caused by cardiac structural abnormalities and/or functional impairments. In general, HF is a chronic, progressive condition associated with significant morbidity and mortality. Main treatments include healthy lifestyle changes, in some cases surgery and implantation of devices to control heart rhythm, and pharmacotherapy. Prescribed drugs for heart failure with reduced ejection fraction (HFrEF) include angiotensin‐converting enzyme inhibitors, angiotensin‐2 receptor blockers (ARBs) or an angiotension receptor neprilysin inhibitor (ARNI), beta blockers, mineralocorticoid receptor antagonists, diuretics, and more recently SGLT‐2 (sodium glucose co‐transporter‐2) inhibitors. However, even with these new entrants and optimal guideline‐directed medical therapy, event rates in HFrEF remain as high as 15% per year of the composite outcome CV death or HF hospitalization in the empagliflozin arm of EMPEROR‐REDUCED [4] and even 38% in patients with HFrEF after a previous event in the placebo group of VICTORIA [5]. Therefore, the unmet need in HF is still high and drugs targeting other pathways involved in disease progression are sought. No less than 1 out of 6 patients suffering from HFrEF develop worsening HF on average 1.5 years following initial HF diagnosis. The high risk for two‐year mortality and recurrent HF hospitalizations in these patients indicates particularly high unmet medical need for novel treatment strategies [1]. Here we present the discovery and development of the soluble guanylate cyclase (sGC) stimulator vericiguat (BAY 1021189; MK‐1242) for the treatment of chronic HF. Data from the phase 3 VICTORIA trial in patients with worsening chronic HF and ejection fraction <45% were published in the New England Journal of Medicine [5, 6]. Vericiguat 10 mg once daily significantly reduced the combined risk of first HF hospitalization or CV death (Figure 3.1).

Figure 3.1 sGC stimulator vericiguat.

3.2 Soluble Guanylate Cyclase Stimulators as Treatment Option for Heart Failure

The nitric oxide (NO)/sGC/cGMP pathway is one of the major signaling cascades for regulation of cardiopulmonary, vascular and renal function (Figure 3.2) [7, 8]. This signaling pathway is triggered by the production of NO via NO synthases. NO, which is a gas, can pass cellular membranes and binds to the cytosolic sGC which carries an NO‐binding heme structure in the beta subunit of the enzyme. NO binding to sGC triggers a conformational change of the enzyme and an activation of the catalytic site which transfers GTP in the second messenger molecule cGMP which binds and activates several downstream targets, e.g. the cGMP‐activated protein kinases (PKG1 and PKG2) [9]. Impairment and disruption of the NO/cGMP pathway which is characterized by a decline in cGMP production causing the abrogation of cGMP downstream signaling, contributes to the development and progression of CV diseases including HF [10]. The pathophysiology of CV diseases includes endothelial cell dysfunction which impairs NO production leading to decreased NO availability and reduced cGMP tissue levels. This reduced NO availability and insufficient stimulation of sGC results in systemic, vascular dysregulation, affecting the coronary, pulmonary, and renal circulation. Moreover, impaired sGC signaling is leading to organ damage and dysfunction of the heart. Therefore, it is an intriguing therapeutic concept to restore cGMP signaling via direct stimulation of sGC with the novel, NO‐independent sGC stimulator vericiguat [11, 12]. Vericiguat has been shown to directly bind to sGC and stimulates the enzyme also in the absence of NO. In addition, vericiguat could enhance the efficacy of endogenous NO. Thus, vericiguat is able to restore impaired cGMP signaling in chronic HF. This unique mode of action makes vericiguat a promising molecule for the treatment of CV disease including HF.

Figure 3.2 The NO/sGC signaling and natriuretic peptide/pGC signaling with major pharmacological intervention sites. Abbreviations: ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; GTP, guanosine triphosphate; NEP, neutral endopeptidase; NO, nitric oxide; NOS, nitric oxide synthase; NP, natriuretic peptide; PDE, phosphodiesterase; pGC, particulate guanylate cyclase; sGC, soluble guanylate