The success of antitumor and antiviral vaccines often requires the use of an adjuvant, a substance that significantly enhances the immune response to a co-administered antigen. Only a handful of adjuvants have both sufficient potency and acceptable toxicity for clinical investigation. One promising adjuvant is QS-21, a saponin natural product that is the immunopotentiator of choice in many cancer and infectious disease vaccine clinical trials. However, the therapeutic promise of QS-21 adjuvant is curtailed by several factors, including its scarcity, difficulty in purification to homogeneity, dose-limiting toxicity, and chemical instability. Here we report the design, synthesis, and evaluation of chemically stable synthetic saponins. These novel, amide-modified, non-natural substances exhibit immunopotentiating effects in vivo that rival or exceed that of QS-21 in evaluations with the GD3-KLH melanoma conjugate vaccine. The highly convergent synthetic preparation of these novel saponins establishes new avenues for discovering improved molecular adjuvants for specifically tailored vaccine therapies.

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...

Certain members of the crambescidin natural products, [1][2][3][4][5] derived from the marine sponge Crambe crambe, have exhibited remarkable biological properties, including anticancer, anti-HIV, antifungal, and Ca 2+ ion channel blocking activities. Many compounds within this class are characterized by a polycyclic guanidine core linked to a hydroxyspermidine moiety by a linear ω-hydroxy fatty acid. Crambidine (1, Figure 1) is atypical within this family of alkaloids in that it possesses a fused pyrimidine heterocyclic core, while most of its other congeners exist in more highly reduced forms. Several elegant strategies have been reported for the synthesis of crambescidin alkaloids. 6-9 However, only a single reported synthesis of crambidine (1) has appeared, 10 involving dihydropyrimidine construction via Biginelli condensation, followed by oxidation. We report herein a synthesis of (-)-crambidine that capitalizes on two key processes, including a [4+2] annulation of thioimidates with vinyl carbodiimides and a hydroamination of alkynes with 2-aminopyrimidine nucleophiles.

PARP14 is an interferon‐stimulated gene that is overexpressed in multiple tumor types, influencing pro‐tumor macrophage polarization as well as suppressing the antitumor inflammation response by modulating IFN‐γ and IL‐4 signaling. PARP14 is a 203 kDa protein that possesses a catalytic domain responsible for the transfer of mono‐ADP‐ribose to its substrates. PARP14 also contains three macrodomains and a WWE domain which are binding modules for mono‐ADP‐ribose and poly‐ADP‐ribose, respectively, in addition to two RNA recognition motifs. Catalytic inhibitors of PARP14 have been shown to reverse IL‐4 driven pro‐tumor gene expression in macrophages, however it is not clear what roles the non‐enzymatic biomolecular recognition motifs play in PARP14‐driven immunology and inflammation. To further understand this, we have discovered a heterobifunctional small molecule designed based on a catalytic inhibitor of PARP14 that binds in the enzyme's NAD+‐binding site and recruits cereblon to ubiquitinate it and selectively target it for degradation.

PurposeThe nitric oxide (NO)–cyclic guanosine-3′,5′-monophosphate (cGMP) pathway regulates aqueous humor outflow and therefore, intraocular pressure. We investigated the pharmacologic effects of the soluble guanylate cyclase (sGC) stimulator IWP-953 on primary human trabecular meshwork (HTM) cells and conventional outflow facility in mouse eyes.MethodsCyclic GMP levels were determined in vitro in HEK-293 cells and four HTM cell strains (HTM120/HTM123: predominantly myofibroblast-like phenotype, HTM130/HTM141: predominantly endothelial-like phenotype), and in HTM cell culture supernatants. Conventional outflow facility was measured following intracameral injection of IWP-953 or DETA-NO using a computerized pressure-controlled perfusion system in enucleated mouse eyes ex vivo.ResultsIWP-953 markedly stimulated cGMP production in HEK-293 cells in the presence and absence of DETA-NO (half maximal effective concentrations: 17 nM, 9.5 μM). Similarly, IWP-953 stimulated cGMP production in myofibroblast-like HTM120 and HTM123 cells, an effect that was greatly amplified by the presence of DETA-NO. In contrast, IWP-953 stimulation of cGMP production in endothelial-like HTM130 and HTM141 cells was observed, but was markedly less prominent than in HTM120 and HTM123 cells. Notably, cGMP was found in all HTM culture supernatants, following IWP-953/DETA-NO stimulation. In paired enucleated mouse eyes, IWP-953 at 10, 30, 60, and 100 μM concentration-dependently increased outflow facility. This effect (89.5%) was maximal at 100 μM (P = 0.002) and in magnitude comparable to DETA-NO at 100 μM (97.5% increase, P = 0.030).ConclusionsThese data indicate that IWP-953, via modulation of the sGC–cGMP pathway, increases aqueous outflow facility in mouse eyes, suggesting therapeutic potential for sGC stimulators as novel ocular hypotensive drugs.