Cyanoguanidine Derivatives Research Articles

Discovery of cyanoguanidine derivatives as biased μ-opioid receptor agonists

Opioid agonists, including morphine and its derivatives, have historically been utilized in conventional pain relief therapies. However, the morphine-like side effects associated with these compounds have constrained their broader application in clinical environments. Fortunately, novel compounds that selectively activate μ-opioid receptors (MOR) without activating the β-arrestin2 pathway, such as PZM21 and TRV130, demonstrate the potential to mitigate side effects while maintaining analgesic efficacy. In this study, we structurally modified PZM21 to get a series of compounds with a 2-cyanoguanidine scaffold, the majority of which display significant analgesic effects. Notably, Compound I-11 exhibited an analgesic effect comparable to that of morphine and selectively activates μ-opioid receptors while avoiding the activation of the β-arrestin2 pathway. Our work not only introduces a novel biased μ-opioid receptor agonist but also serves as a valuable reference for the further optimization of PZM21.

Fluorophenylalkyl-substituted cyanoguanidine derivatives as bacteria-selective MATE transporter inhibitors for the treatment of antibiotic-resistant infections

Drug efflux pump inhibitors for the multidrug resistance protein HmrM, a member of the multidrug and toxin extrusion (MATE) family of transporters, were investigated to increase the drug susceptibility of multidrug-resistant bacteria and restore the antimicrobial effect of fluoroquinolones, such as norfloxacin. The lead inhibitor, prepared from the known hMATE1 inhibitor cimetidine, reduced the norfloxacin resistance of HmrM-expressing strains by 92% at non-cytotoxic concentrations in human cells, and multidrug resistance protein MdtK-expressing strains by 86%. These results indicated that the inhibitor is a lead candidate for the development of drugs with a novel mechanism of action against infections caused by multidrug-resistant bacteria that act synergistically with antimicrobial drugs.

Preparation of diethylcyanamide and cyanoguanidine complexes of manganese and rhenium

Diethycyanamide complexes [M(NCNEt2)(CO)nL5−n]BPh4 (1a–5a) [M = Mn, Re; n = 1, 2, 3; L = PPh(OEt)2, P(OEt)3] were prepared by allowing hydrides MH(CO)nL5−n to react first with triflic acid (HOTf) and then with an excess of diethylcyanamide. The related cyanoguanidine derivatives [M{NCN(H)C(NH2)NH}(CO)nL5−n]BPh4 (1b–4b) were prepared by reacting hydrides MH(CO)nL5−n first with an equivalent of HOTf and then with an excess of cyanamide NCNH2 or, alternatively, with cyanoguanidine. Bis(diethylcyanamide) complexes MBr(NCNEt2)2(CO)3 (6, 7) were prepared by allowing pentacarbonyl species MBr(CO)5 to react with an excess of cyanamide NCNEt2. The complexes were characterised by spectroscopy (IR, 1H, 31P, 13C NMR) and by X-ray crystal structure determination of [Mn(NCNEt2)(CO)2{PPh(OEt)2}3]BPh4 (2a) and ReBr(NCNEt2)2(CO)3 (7a).

Synthesis and Dual Histamine H1 and H2 Receptor Antagonist Activity of Cyanoguanidine Derivatives

Premedication with a combination of histamine H1 receptor (H1R) and H2 receptor (H2R) antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H1R and H2R antagonistic activity, a series of cyanoguanidines 14–35 was synthesized by linking mepyramine-type H1R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H2R antagonist moieties. N-desmethylmepyramine was connected via a poly-methylene spacer to a cyanoguanidine group as the “urea equivalent” of the H2R antagonist moiety. The title compounds were screened for histamine antagonistic activity at the isolated ileum (H1R) and the isolated spontaneously beating right atrium (H2R) of the guinea pig. The results indicate that, depending on the nature of the H2R antagonist partial structure, the highest H1R antagonist potency resided in roxatidine-type compounds with spacers of six methylene groups in length (compound 21), and tiotidine-type compounds irrespective of the alkyl chain length (compounds 28, 32, 33), N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-N″-[2-[N-[2-[N-(4-methoxybenzyl)-N-(pyridyl)-amino] ethyl]-N-methylamino]ethyl] guanidine (25, pKB values: 8.05 (H1R, ileum) and 7.73 (H2R, atrium) and the homologue with the mepyramine moiety connected by a six-membered chain to the tiotidine-like partial structure (compound 32, pKB values: 8.61 (H1R) and 6.61 (H2R) were among the most potent hybrid compounds. With respect to the development of a potential pharmacotherapeutic agent, structural optimization seems possible through selection of other H1R and H2R pharmacophoric moieties with mutually affinity-enhancing properties.

ChemInform Abstract: Synthesis and Biological Evaluation of Cyanoguanidine Derivatives of Loratadine.

AbstractDesloratadine (I), synthesized according to previously published methods, is reacted with thioates (II) to yield the target compounds (III).

Synthesis and biological evaluation of cyanoguanidine derivatives of loratadine

Cyanoguanidine derivatives of loratadine (3a–i) were synthesized and screened for antitumor and anti-inflammatory activity. The most promising compound 3c (R=n-C8H17) possessed at least twofold higher in vitro cytotoxicity than 5-fluorouracil against mammary (MCF-7 and MDA-MB 231) as well as colon (HT-29) carcinoma cells. The mode of action, however, is so far unclear. The participation of the COX-1/2 enzymes on the cytotoxicity, however, is very unlikely. Nevertheless all compounds showed stronger in vivo anti-inflammatory activity than ibuprofen in the xylene-induced ear swelling assay in mice.

Inhibitory effects of the ATP-sensitive potassium channel openers cromakalim, pinacidil and minoxidil on the carbachol–response curve in porcine detrusor muscle

AimsATP-sensitive potassium channels represent promising drug targets for treating specific bladder diseases. The inhibitory effects of ATP-selective potassium channel openers (PCOs) on the carbachol–response curve in porcine detrusor muscle were examined. Materials and methodsEach of the three substances used in the study represent one prototype of a different class of PCO: cromakalim belongs to the benzopyran series, pinacidil is a cyanoguanidine derivative, and minoxidil represents a pyrimidine derivative. The porcine detrusor muscle represents one of the best models for human detrusor. Experiments were conducted on muscle strips of porcine detrusor muscle suspended in a tissue bath. Concentration–response curves of carbachol were constructed after pretreatment with cromakalim at 10−7, 10−6 and 10−5M, and with pinacidil and minoxidil at 10−6, 10−5.5 and 10−5M, respectively. Each muscle strip was only used to examine one concentration of one substance. ResultsCromakalim had the greatest inhibitory effect, significantly suppressing the carbachol–response curve at 10−6 and 10−5M. Pinacidil showed a significant inhibitory effect at 10−5.5 and 10−5M, which was smaller than that of cromakalim. Minoxidil did not significantly inhibit the contractions at all examined concentrations. ConclusionsThe examined ATP-sensitive PCOs belonging to the benzopyrans and cyanoguanidines significantly suppressed detrusor contractions. The development of derivatives of these prototypes could open new possibilities for the pharmacological treatment of selected bladder diseases.

Exploring QSARs for Inhibitory Activity of Cyclic Urea and Nonpeptide-Cyclic Cyanoguanidine Derivatives HIV-1 Protease Inhibitors by Artificial Neural Network

Quantitative structure–activity relationship study using artificial neural network (ANN) methodology were conducted to predict the inhibition constants of 127 symmetrical and unsymmetrical cyclic urea and cyclic cyanoguanidine derivatives containing different substituent groups such as: benzyl, isopropyl, 4-hydroxybenzyl, ketone, oxime, pyrazole, imidazole, triazole and having anti-HIV-1 protease activities. The results obtained by artificial neural network give advanced regression models with good prediction ability. The two optimal artificial neural network models obtained have coefficients of determination of 0.746 and 0.756. The lowest prediction’s root mean square error obtained is 0.607. Artificial neural networks provide improved models for heterogeneous data sets without splitting them into families. Both the external and cross-validation methods are used to validate the performances of the resulting models. Randomization test is employed to check the suitability of the models.

Antitumor effect of BPR-DC-2, a novel synthetic cyclic cyanoguanidine derivative, involving the inhibition of MDR-1 expression and down-regulation of p-AKT and PARP-1 in lung cancer

In our previous study, a series of novel cyclic cyanoguanidine compounds, eg. 5-substituted 2-cyanoimino-4-imidazodinone and 2-cyanoimino-4- pyrimidinone derivatives have been successfully synthesized and showed remarkable cytotoxicity in several cancer cell lines. In this present study, it is our aim to screen more potential candidates among the cyclic pyridyl cyanoguanidine compounds (BPR-DC-1, 2, 3) by in vitro and in vivo studies for the therapy of lung cancer, alternatively. Our results showed that BPR-DC-2 significantly inhibited proliferation of tumor cells with an IC50 of 3.60 ± 1.27 and 14.81 ± 4.23 μM in human lung carcinoma cells, H69 and A549, respectively by the MTT assay at 48 hr; BPR-DC-2 also obviously suppressed the tumor proliferation and MDR-1 gene expression, even induced cell apoptosis in the ex vivo histocultured lung tumor. We further demonstrated that, in the nude mouse model of metastatic lung cancer, BPR-DC-2 could diminish the tumor mass, retard the progression of metastasis, and prolong the survival time. In addition, it was found that BPR-DC-2 exerted its anti-tumor effects through the inhibition of MDR-1 gene expression and down-regulation of tumor anti-apoptosis signals (activated p-AKT and over-expression of PARP-1) by western blotting analysis. In conclusion, in this present study we have demonstrated that BPR-DC-2, derived from a series of novel synthetic cyclic cyanoguanidine compounds, has proved its potential as an anti-tumor drug candidate in treating lung cancer.

Modulatory action of potassium channel openers on field potential and histamine release from rat peritoneal mast cells

To determine whether changes in membrane potential affect the extent of mast cell degranulation, compound 48/80 was added to rat peritoneal mast cell suspensions in the absence or presence of potassium channel openers (KCOs). Changes were compared between the field potential (FP) and the amount of histamine released. The results demonstrated that (i) the onset and duration of FP, which reflects the hyperpolarizing nature of the response, increased as the concentration of compound 48/80 increased; (ii) both FP and the amount of histamine released increased as the concentration of compound 48/80 increased; (iii) although both KCOs (SDZ PCO400, a benzopyran derivative, and P1060, a cyanoguanidine derivative) potentiated compound 48/80-induced increases in FP and histamine release, without compound 48/80, they had no effect on either parameter; (iv) both glibenclamide and charybdotoxin significantly attenuated the compound 48/80-induced increase in FP; and (v) glibenclamide was able to attenuate the KCO-induced potentiation of FP. The results show that drugs presumably causing hyperpolarization can affect histamine release from rat peritoneal mast cells. The effect of KCOs on compound 48/80-induced response appears to be potentiation in nature rather than synergism. It is possible that KCO hyperpolarizes the cell membrane, enhances Ca2+ influx, and thus increases histamine release. As such, selective blockers of K+ channels may be useful for the treatment of immunological disorders.

The use of microelectrode array (MEA) to study the protective effects of potassium channel openers on metabolically compromised HL-1 cardiomyocytes

The microelectrode array (MEA) was used to evaluate the cardioprotective effects of adenosine triphosphate sensitive potassium (KATP) channel activation using potassium channel openers (KCOs) on HL-1 cardiomyocytes subjected to acute chemically induced metabolic inhibition. Beat frequency and extracellular action potential (exAP) amplitude were measured in the presence of metabolic inhibitors (sodium azide (NaN3) or 2-deoxyglucose (2-DG)) or KCOs (pinacidil (PIN, a cyanoguanidine derivative, activates sarcolemmal KATP channels) or SDZ PCO400 (SDZ, a benzopyran derivative, activates mitochondrial KATP channels)). The protective effects of these KCOs on metabolically inhibited HL-1 cells were subsequently investigated. Signal shapes indicated that NaN3 and 2-DG reduced the rate of the sodium (Na+) influx signal as reflected by a reduction in beat frequency. PIN and SDZ appeared to reduce both rate of depolarization and extent of the Na+ influx signals. Pre-treating cardiomyocytes with PIN (0.1 mM), but not SDZ, prevented the reduction of beat frequency associated with NaN3- or 2-DG-induced metabolic inhibition. The exAP amplitude was not affected by either KCO. The cardioprotective effect of PIN relative to SDZ may be due to the opening of different KATP channels. This metabolic inhibition model on the MEA may provide a stable platform for the study of cardiac pathophysiology in the future.

Structure−Activity Studies of Novel Cyanoguanidine ATP-Sensitive Potassium Channel Openers for the Treatment of Overactive Bladder

A series of novel cyanoguanidine derivatives was designed and synthesized. Condensation of N-(1-benzotriazol-1-yl-2,2-dichloropropyl)-substituted benzamides with N-(substituted-pyridin-3-yl)-N'-cyanoguanidines furnished N-{2,2-dichloro-1-[N'-(substituted-pyridin-3-yl)-N''-cyanoguanidino]propyl}-substituted benzamide derivatives. These agents were glyburide-reversible potassium channel openers and hyperpolarized human bladder cells as assessed by the FLIPR membrane potential dye (KATP-FMP). These compounds were also potent full agonists in relaxing electrically stimulated pig bladder strips, an in vitro model of overactive bladder. The most active compound 9 was evaluated for in vivo efficacy and selectivity in a pig model of bladder instability. Preliminary pharmacokinetic studies in dog demonstrated excellent oral bioavailability and a t1/2 of 15 h. The synthesis, SAR studies, and biological properties of these agents are discussed.

Novel P2X7 receptor antagonists ease the pain

In recent months, a series of chemically diverse antagonists has been identified for the ATP-gated P2X(7) receptor. In particular, two classes of highly-selective competitive P2X(7) antagonists have been developed by Michael Jarvis and his colleagues at Abbott Laboratories. These di-substituted tetrazole and cyanoguanidine derivatives are outstanding for a number of reasons (not least their stability, selectivity, potency and, of course, reversibility); most exciting is their near equal potency at human and rodent P2X(7) isoforms. Armed with drugs such as A740003 and newer A438079, Jarvis and colleagues have explored the role of P2X(7) receptors in the onset and persistence of chronic pain in animal models. Their findings - and applicability to the human condition - are reviewed in this current issue of British Journal of Pharmacology. This accompanying Commentary describes the progress made by Jarvis and others in developing novel P2X(7) antagonists for pain relief.

Synthesis and Analgesic Activity Evaluation of Some Agmatine Derivatives

A series of N,N'-disubstituted-2-nitroethene-1,1-diamine and N,N'-disubstituted- N''-cyanoguanidine derivatives were prepared and evaluated for in vivo analgesic activity. The blood brain barrier (BBB) VolSurf model was used to predict the BBB permeation profiles of our synthesized compounds. Some compounds show both remarkable analgesic activity and good BBB permeation profiles, and these compounds might be developed for treatment of opioid tolerance and dependence.

Quantitative structure-activity relationship by CoMFA for cyclic urea and nonpeptide-cyclic cyanoguanidine derivatives on wild type and mutant HIV-1 protease

3D-QSAR studies using the Comparative Molecular Field Analysis (CoMFA) methodology were conducted to predict the inhibition constants, K(i), and the inhibitor concentrations, IC90 of 127 symmetrical and unsymmetrical cyclic urea and cyclic cyanoguanidine derivatives containing different substituent groups such as: benzyl, isopropyl, 4-hydroxybenzyl, ketone, oxime, pyrazole, imidazole, triazole and having anti-HIV-1 protease activities. A significant cross-validated correlation coefficient (q2) of 0.63 and a fitted correlation coefficient r2 of 0.70 were obtained, indicating that the models can predict the anti-protease activity from poorly to highly active compounds reliably. The best predictions were obtained for: XV643 (predicted log 1/K(i) = 9.86), a 3,5-dimethoxy-benzyl cyclic urea derivate (molec60, predicted log 1/K(i) = 8.57) and a benzyl cyclic urea derivate (molec 61, predicted log 1/IC90 = 6.87). Using the CoMFA method, we also predicted the biological activity of 14 cyclic urea derivatives that inhibit the HIV-1 protease mutants V82A, V82I and V82F. The predicted biological activities of the: (i) XNO63 (inhibitory activity on the mutant HIV-1 PR V82A), (ii) SB570 (inhibiting the mutant HIV-1 PR V82I) and also (iii) XV652 (during the interaction with the mutant HIV-1 PR V82F) were in good agreement with the experimental values.

Insecticidal and Neuroblocking Activities of Thiacloprid and Its Acyclic Analogues and Their Related Cyanoguanidine Derivatives

チアクロプリドの非環状類縁体およびシアノグアニジン関連化合物を合成し, それらのワモンゴギブリに対する殺虫活性を化合物単独, あるいは代謝阻害剤を併用して注射法により測定した. 単独の場合には, チアクロプリドと2種のシアノグアニジン誘導体が最も高い活性を示し, イミダクロプリドの20分の1程度であった. チアクロプリドを含む含硫黄化合物の活性は, 代謝阻害剤の併用により100倍位にまで増大した. 他方, シアノグアニジン誘導体の場合には, 代謝阻害剤による増大効果ははるかに小さかった. ワモンゴキブリの摘出神経に対しては, ほとんどの供試化合物は最初興奮を誘起した後, 遮断効果をもたらした. チアクロプリドとその非環状類縁体の遮断活性は, イミダクロプリドのものに匹敵していた. 全体としては遮断活性が高いほど, 代謝阻害剤併用条件下での殺虫活性が高くなる傾向が見られた.

Preparation of Novel Cyanoguanidine Derivatives of Tryptamines

Preparation of Novel Cyanoguanidine Derivatives of Tryptamines

Inhibitors of farnesyl protein transferase. synthesis and biological activity of amide and cyanoguanidine derivatives containing a 5,11-dihydro[1]benzthiepin, benzoxepin, and benzazepin [4,3- b]pyridine ring system

Bioisosteric replacement of the C-6 carbon atom in piperidine I and piperazine II with S, O, and N heteroatoms is described. Amide and cyanoguanidine derivatives of these compounds were evaluated in vitro and found to be good inhibitors of farnesyl-protein transferase. An improved method of preparing the 5,11-dihydro-[1]-benzthiepin nucleus 6 was accomplished in high yield and with excellent regioselectivity using an AlCl 3 melt protocol.

ChemInform Abstract: Novel Potassium‐Channel Openers: Preparation and Pharmacological Evaluation of Racemic and Optically Active N‐(6‐Amino‐3‐pyridyl)‐N′‐ bicycloalkyl‐N′′‐cyanoguanidine Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Novel potassium-channel openers: preparation and pharmacological evaluation of racemic and optically active N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives.

The previous paper reported on the synthesis and pharmacological evaluation of N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives, from among which three compounds were selected as potent potassium-channel openers. In the present study, selected compounds were tested for antagonism of potassium-induced contraction of rat aorta, hypotensive activity in normotensive rats, and diuretic activity in spontaneously hypertensive rats. This led to further evaluation of compound (+/-)-10 and selection of (+)-N-(6-amino-3-pyridyl)-N'- [(1S,2R,4R)-bicyclo- [2.2.1]hept-2-yl]-N"-cyanoguanidine ((+)-10) (AL0670) for development as an antihypertensive agent. Although AL0670 is regarded as a pinacidil-type K(+)-channel opener, it showed different pharmacological and conformational profiles from pinacidil.