Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impaired bioavailability and/or responsiveness to endogenous NO has been implicated in the pathogenesis of cardiovascular and other diseases. Current therapies that involve the use of organic nitrates and other NO donors have limitations, including non-specific interactions of NO with various biomolecules, lack of response and the development of tolerance following prolonged administration. Compounds that activate sGC in an NO-independent manner might therefore provide considerable therapeutic advantages. Here we review the discovery, biochemistry, pharmacology and clinical potential of haem-dependent sGC stimulators (including YC-1, BAY 41-2272, BAY 41-8543, CFM-1571 and A-350619) and haem-independent sGC activators (including BAY 58-2667 and HMR-1766).

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NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential

Soluble guanylate cyclase (sGC), a key enzyme of the nitric oxide (NO) signaling pathway, is attracting rapidly growing interest as a therapeutic target in cardiopulmonary disease, with several sGC agonists currently in clinical development. On binding of NO to a prosthetic heme group on sGC, the enzyme catalyzes synthesis of the second messenger cGMP, which produces vasorelaxation and inhibits smooth muscle proliferation, leukocyte recruitment, and platelet aggregation through a number of downstream mechanisms.1,2

Impaired NO and cGMP signaling has been implicated in the pathogenesis of cardiovascular disease, including systemic arterial and pulmonary hypertension (PH), coronary artery disease, peripheral vascular disease (including erectile dysfunction), and atherosclerosis.1,3,–,5 Organic nitrates that target the NO signaling pathway have been used to treat cardiovascular disease for >150 years. More recently, gaseous NO administered by inhalation has been approved for the treatment of persistent PH of the newborn.3,6 These agents nonetheless have several important limitations. Cardiovascular disease is associated with resistance to NO and organic nitrates.7 This may be due to the oxidative stress–induced alteration of the redox state of the prosthetic heme on sGC (from ferrous to ferric) that weakens the binding of heme to the enzyme and renders sGC unresponsive to NO.1,8 Furthermore, the long-term efficacy of organic nitrates is limited by the development of tolerance.9 Nitric oxide may also have numerous cytotoxic effects, mostly attributed to the reactive oxidant peroxynitrite (formed from the diffusion-controlled reaction of NO with superoxide).3,10 Peroxynitrite interacts with proteins and lipids, altering cellular signaling, disrupting mitochondrial function, and damaging DNA, which can eventually culminate in cellular dysfunction and/or death.3

Because the beneficial effects of NO appear to be …

Soluble Guanylate Cyclase as an Emerging Therapeutic Target in Cardiopulmonary Disease

Direct and rapid heating by microwave irradiation in combination with sealed vessel processing in many cases enables reactions to be carried out in a fraction of the time generally required using conventional conditions. This makes microwave chemistry an ideal tool for rapid reaction scouting and optimization of conditions, allowing very rapid progress through hypotheses–experiment–results iterations. The speed at which multiple variations of reaction conditions can be performed allows a morning discussion of “What should we try?” to become an after-lunch discussion of “What were the results” Not surprisingly, therefore, many scientists both in academia and industry have turned to microwave synthesis as a front-line methodology for their projects. In this review, more than 220 published examples of microwave-assisted synthetic organic transformations from the 2004 to 2008 literature are discussed. An additional ca. 500 reaction schemes are presented in the Electronic Supplementary Material, providing the reader with an overall number of ca. 930 references in this fast-moving and exciting field.

Controlled microwave heating in modern organic synthesis: highlights from the 2004–2008 literature

Protein kinases have become the second most exploited group of drug targets after G-protein-coupled receptors (GPCRs), accounting for 30% of drug discovery projects at many pharmaceutical companies with dozens of compounds in clinical development. Most early kinase inhibitors exhibited poor selectivity between kinases, and the trend in recent years has been toward ever more selective inhibitors in an attempt to minimize the risk of side effects. The risk with highly selective inhibitors is that their efficacy for treating complex diseases like cancer might be compromised by the redundancies in signaling pathways. The increasing interest in multitarget drug discovery (MTDD) stems froma belief that modulating more than one target can provide superior efficacy and safety profiles compared to single target drugs. Currently, there are two contrasting MTDD philosophies. The first involves combining agents that are selective for a single target to achieve an additive or synergistic effect. The second involves discovering agents that are simultaneously capable of addressing two or more targets. Although this perspective focuses primarily on the latter, the advantages and disadvantages of both approaches will be highlighted. Very few drugs are truly selective for a single target, and in reality most biologically active small molecules have a degree of promiscuity by their very nature. Many clinically useful drugs are now known to have multiple activities, but most of these multitarget drugs (MTDs) were discovered serendipitously and their mechanisms of action were only established retrospectively. The deliberate and prospective design of ligands that act in a “selectively nonselective” manner on multiple targets of therapeutic interest is an emerging trend in drug discovery. Increasing numbers of these so-called designed multiple ligands (DMLs) are being reported in the medicinal chemistry literature. In particular, identifying multikinase inhibitors (MKIs) with specific multiple activity profiles is currently an area of great interest in the pharmaceutical industry, especially for the treatment of cancer. Five years ago there were few examples of DMLs in the medicinal chemistry literature for kinase targets, but the period since has witnessed an explosive growth in interest in this area. Marketed MKI drugs vary with respect to the number of kinases they are known to inhibit, with some inhibiting only a small number of kinases, whereas others appear to be highly promiscuous. These apparent differences in selectivity are to an extent influenced by the amount of selectivity screening that has been performed,with some inhibitors appearing to be more promiscuous simply on the basis of having been profiled more rigorously. As the title of this Perspective delineates, the aim for themedicinal chemistworking in theMKI field should be to strike the right balance between the nonselectivity (promiscuity) that may be required for efficacy and the selectivity that is required for safety. At present it is difficult to intentionally design aMKIwith activity only at the kinases of interest, but increasingly rational and elegant medicinal chemistry approaches are being applied to solving this difficult problem. This Perspective aims to capture the current state of the art and to explore the future challenges and strategies in this area. The terminology used herein, illustrated using known inhibitors, is summarized in Figure 1.

Selectively nonselective kinase inhibition: striking the right balance.

Sulfone derivatives are important synthetic intermediates. However, the general method for their preparation is through traditional coupling reaction: the alkylation of sodium sulfinates with phenacyl halides. Based on our previous work on sodium sulfinates and oxime acetates, we herein report a novel method for sulfone derivatives by oxidative coupling with sodium sulfinates and oxime acetates using copper as catalyst. The sulfonylvinylamine products could be formed in excellent yields. Upon hydrolysis by silica gel in CH2 Cl2 , β-ketosulfones could also be efficiently constructed. Various sulfonylvinylamines and β-ketosulfones were obtained in good to excellent yields under the optimized reaction conditions. Mechanistic studies indicated that this transformation involved copper-catalyzed N-O bond cleavage, activation of a vinyl sp(2) C-H bond, and C-S bond formation. The oxime acetates act as both a substrate and an oxidant, thus the reaction needs no additional oxidants or additives.

Copper‐Catalyzed Coupling of Oxime Acetates with Sodium Sulfinates: An Efficient Synthesis of Sulfone Derivatives

A short and versatile synthesis of substituted quinolines is provided. Alkylation of sodium tolylsulfinate with bromomethyl- or chloromethyl ketones generates beta-keto sulfones. Knoevenagel condensation of the beta-keto sulfones with an aldehyde provides alpha-tolylsulfonyl-alpha,beta-unsaturated ketones. Michael addition of the dianion of N-Boc-anilines in the presence of CuCN and LiCl with the unsaturated ketone generates a 1,4-adduct, which after deprotection of the Boc group and thermal elimination of the tolyl sulfone provides the quinoline.

Synthesis of substituted quinolines using the dianion addition of N-Boc-anilines and alpha-tolylsulfonyl-alpha,beta-unsaturated ketones.

Compounds of formula (I), compounds of formula (II), compounds of formula (III), and compounds of formula (IV), or pharmaceutically acceptable salts thereof are useful as H3 receptor antagonists. Processes to make the compounds and methods of treatment using the compounds are also disclosed.

Cyclic and bicyclic diamino histamine-3 receptor antagonists

The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg·day po). The compound was docked into a homology model of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improve its cardiac safety profile. Systematic interruption of key binding interactions between 8 and Phe656, Tyr652, and Ser624 yielded 90, which only showed an IC50 of 11.6 μM in the hERG patch clamp assay. The selectivity profile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors with low nanomolar potencies against the members of the VEGFR and PDGFR kinase ...

1,4-Dihydroindeno[1,2-c]pyrazoles with acetylenic side chains as novel and potent multitargeted receptor tyrosine kinase inhibitors with low affinity for the hERG ion channel.

The present invention relates to the use of compounds of formula (I), for the treatment of sexual dysfunction and to compositions containing compounds of formula (I) for the treatment of sexual dysfunction.

Henry Q. Zhang

Papers

Synthesis of substituted quinolines using the dianion addition of N-Boc-anilines and alpha-tolylsulfonyl-alpha,beta-unsaturated ketones.

Cyclic and bicyclic diamino histamine-3 receptor antagonists

1,4-Dihydroindeno[1,2-c]pyrazoles with acetylenic side chains as novel and potent multitargeted receptor tyrosine kinase inhibitors with low affinity for the hERG ion channel.

Acetamides and benzamides that are useful in treating sexual dysfunction

Efficient Pd-catalyzed synthesis of 2-arylaminopyrimidines via microwave irradiation