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PubMed2004

Synthesis and biological activity of novel 1,4-diazepane derivatives as factor Xa inhibitor with potent anticoagulant and antithrombotic activity.

Factor Xa (fXa) is a serine protease involved in the coagulation cascade, which has received great interest as a potential target for the development of new antithrombotic drugs. Herein we report a novel series of fXa inhibitors in which the 1,4-diazepane moiety was designed to interact with the S4 aryl-binding domain of the fXa active site. Compound 13 (YM-96765) showed potent fXa inhibitory activity (IC(50) = 6.8 nM) and effective antithrombotic activity without prolonging bleeding time.

Animals↗
PubMed1999

Pharmacokinetics of the 8-methoxyquinolone, moxifloxacin: tissue distribution in male rats.

BAY 12-8039 (moxifloxacin-HCl) and 14C-labelled BAY 12-8039 were administered to male rats as single i.v. and oral doses of 4.6 and 5.0 mg/kg bodyweight respectively. The distribution of substance-associated radioactivity in the body was investigated by whole-body autoradiography. The concentrations of the unchanged compound in plasma, skin suction blister fluid and lung tissue were determined by HPLC. Whole-body autoradiography revealed distinctly higher concentrations of radioactivity in the gastrointestinal tract, urinary bladder and in most organs and tissues (e.g. kidneys, liver, spleen, lungs, various glands, cartilaginous tissues and in melanin-containing structures located in the eye, meninges and hair follicles of pigmented skin) than in blood. Radioactivity crossed the blood-brain barrier only to a small extent. The results show a high tissue affinity and a rapid and homogeneous distribution of radioactivity from blood to organs or tissues. No relevant difference in the distribution of radioactivity was found following i.v. and oral administration. After i.v. and oral dosing similar concentrations of the unchanged compound were determined in skin suction blister fluid and plasma. The concentrations of the unchanged compound in lung tissue were about three times higher than those in plasma following both i.v. and oral administration. The concentration-time courses for moxifloxacin in plasma and lung tissue were parallel.

Animals↗
PubMed2006

A remarkable inversion of structure-activity dependence on imido N-substituents with varying co-ligand topology and the synthesis of a new borate-free zwitterionic polymerisation catalyst.

Ethylene polymerisation productivities of tris(pyrazolyl)methane-supported catalysts [Ti(NR){HC(Me2pz)3}Cl2] show a dramatically different dependence on the imido R-group compared to those of their TACN analogues, attributed to differences in fac-N3 donor topology; when treated with AliBu3, the zwitterionic tris(pyrazolyl)methide compound [Ti(N-2-C6H4tBu){C(Me2pz)3}Cl(THF)] also acts as a highly active, single site catalyst (TACN = 1,4,7-trimethyltriazacyclononane).

Aza Compounds↗
PubMed2004

Orally active factor Xa inhibitor: synthesis and biological activity of masked amidines as prodrugs of novel 1,4-diazepane derivatives.

Factor Xa (fXa) is a serine protease, which plays a pivotal role in the coagulation cascade. To improve the oral anticoagulant activity of fXa inhibitors containing a 1,4-diazepane moiety as the P4 part, a prodrug strategy was examined. Among the compounds evaluated in this study, amidoxime prodrugs bearing an ester moiety, such as compounds 21 and 30, showed effective oral anticoagulant activity in mice.

Administration, Oral↗
PubMed2002

Diaza- and triazachrysenes: potent topoisomerase-targeting agents with exceptional antitumor activity against the human tumor xenograft, MDA-MB-435.

Several 5,12-diazachrysen-6-ones and 5,6,11-triazachrysen-12-ones were synthesized with varied substituents at the 5- or 11-position, respectively. Each compound was evaluated for its potential to stabilize the cleavable complex formed with TOP1 and DNA. Two analogues with very potent TOP1-targeting activity, 3a and 4a, exhibited cytotoxic activity with IC(50) values at or below 2nM against RPMI8402. Compound 3a was active in vivo by either ip or po administration in the human tumor xenograft athymic nude mice model.

Animals↗
PubMed1990

Comparative actions of immunosuppressants, glucocorticoids and non-steroidal anti-inflammatory drugs on various models of delayed hypersensitivity and on a non-immune inflammation in mice.

Various models of delayed hypersensitivity (DH) were used in mice: contact hypersensitivity reactions to picryl chloride and oxazolone and reactions to methylated bovine serum albumin (MBSA) and sheep red blood cells (SRBC). Drugs of different classes were tested in these models by systemic treatment around the challenge period: non-steroidal anti-inflammatory drugs (cyclooxygenase inhibitors, and inhibitors of both cyclooxygenase and lipoxygenase); glucocorticoids and immunosuppressants (cyclosporin A. CsA; cyclophosphamide, Cy; methotrexate, Mtx; azathioprine, Aza). These compounds were also studied and compared for their effects on the 3-h and 24-h phase of the carrageenin mouse-paw edema (in which inflammation is maximal after 24 h). Non-steroidal anti-inflammatory drugs (including double inhibitors of cyclooxygenase and lipoxygenase) had little or no effect on DH models, except indometacin. Glucocorticoids inhibited all immune reactions except that to MBSA. Of the immunosuppressants, CsA reduced all the DH reactions while Aza mainly reduced the reaction to SRBC; Cy and Mtx were mainly active on SBRC and MBSA inflammations. On another hand CsA, Cy and Mtx were inactive on the 3-h phase but decreased the 24-h phase of carrageenin edema. At doses active on the DH models and on carrageenin inflammation, Cy induced a lasting blood leukopenia, but CsA and Mtx did not. This combination of tests in the mouse seems to be of interest to demonstrate any action on DH and any anti-inflammatory effect and to suggest whether these activities are related to a possible leukopenic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Azanonaboranes containing imidazole derivatives for boron neutron capture therapy: synthesis, characterization, and in vitro toxicity evaluation.

A number of azanonaboranes containing imidazole derivatives have been synthesized by a ligand-exchange reaction. The exo-NH(2)R group of the azanonaborane of the type [(RH(2)N)B(8)H(11)NHR] can be exchanged by one hetero-nitrogen atom of the imidazole ring. In the case of histamine, the exchange takes place on the aliphatic amino group, the hetero-nitrogen atom of the imidazole ring or both of them. The products were confirmed by NMR, IR spectroscopy, elemental analysis, and mass spectrometry. The electron-withdrawing effect of the nitro group in 2-nitroimidazole is the main hindrance to achieve the exchange reaction. In vitro experiments were performed with B16 melanoma cells. A comparison of the biological properties of the products in which the B(8)N cluster is connected to the hetero-nitrogen atom of imidazole ring or the aliphatic NH(2) group showed that incorporation of B(8)N cluster unit into primary amino group increases the compound's toxicity. In contrast, this specificity for cytotoxicity effect was not observed in the case of histamine containing two B(8)N clusters which was relatively nontoxic and did not inhibit colony formation up to concentrations of 2 mM.

Animals↗
PubMed2004

Synthesis and antiproliferative activity of 2,6-diamino-9-benzyl-9-deazapurine and related compounds.

Treatment of 6-bromomethyl- or 6-dibromomethyl-5-nitropyrimidine-2,4-diamine with KCN gave the same product--(2,6-diamino-5-nitropyrimidinyl)acetonitrile. Benzylation of the nitrile took place on the alpha-carbon to the cyano group preferentially affording the corresponding mono- and dibenzyl derivative, whose reductive cyclization resulted in 7-benzyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine and 7,7-dibenzyl-7H-pyrrolo[3,2-d]pyrimidine-2,4,6-triamine, respectively. Suitability of the protection of N(2) and N(4) atoms with benzyl, acetyl, or benzoyl groups was also investigated. The in vitro evaluation of cell growth inhibition on CCRF-CEM, HL-60, HeLa S3, and L1210 cell lines showed significant activity in 8 new compounds. The most potent compounds were the above mentioned 6-dibromomethyl derivative (IC(50)=0.54, 1.7, 5.0, and 1.9 molL(-1)) and 7,N(2),N(4)-tribenzyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine (IC(50)=1.9, 2.7, 7.3, and 1.0 molL(-1)).

Aza Compounds↗
PubMed2003

Structure--activity relationships of azasugar-based MMP/ADAM inhibitors.

In order to investigate structure-activity relationships of azasugar series toward metalloproteinases, we synthesized and evaluated several azasugar-based compounds. As a result, it was found that 4-phenoxybenzene derivative 3 having 2R,3R,4R,5S-configurations exhibited most potent inhibitory activities against matrix metalloproteinase-1, -3 and -9 and TACE.

ADAM Proteins↗
PubMed1992

Tricyclic azaergoline analogues: synthesis, structural modifications, and pharmacological studies.

As an extension of previous investigations on synthesis and dopamine autoreceptor activity of bicyclic ergoline analogues the tricyclic azaergoline analogues 9a and 9b were synthesized. Furthermore, the geometry of the aromatic beta-ethylamine moiety of 9a,b was modified by stereoselective construction of the cycloheptenyl fused pyrazolopyridine derivative 7 and the aminomethyl substituted tricycle 10. Binding affinity of these compounds at dopamine (DA) receptor sites was investigated employing rat striatum homogenate: The compounds reveal modest to weak, but selective binding to a dopamine D-2 receptor when it is labelled with the DA-autoreceptor agonist [3H]-SND 919. In vivo studies with mice showed that 7, 9a,b, and 10 affect their CNS activity.

Animals↗
PubMed1978

Synthesis and analgetic activity of some 5-aryl-2azabicyclo[3.2.1]octanes.

A series of 5-aryl-2-azabicyclo[3.2.1]octanes II has been synthesized and evaluated for analgetic agonist-antagonist activity. These compounds can be regarded as five-membered, conformationally more rigid analogues of the potent agonist-antagonist (-)-5-(3-hydroxyphenyl)-2-methylmorphan (I). Several of these compounds have demonstrated marked analgesic potency comparable to morphine in the mouse writhing assay. Structure-activity correlations, generated by varying N-substitution and O-acetylation of the phenolic function, seem to indicate that optimum activity is associated with an arylethyl side chain attached to the basic nitrogen. Among the most interesting compounds in this series are the phenethyl analogue 31 and its O-acetate 39; the former shows the profile of a well-balanced analgetic-antagonist virtually devoid of physical dependence liability as demonstrated in the rat infusion test.

Analgesics↗
PubMed1999

Synthesis of 2'-methylene-substituted 5-azapyrimidine, 6-azapyrimidine, and 3-deazaguanine nucleoside analogues as potential antitumor/antiviral agents.

2'-Deoxy-2'-methylene-6-azauridine (5) and 2'-deoxy-2'-methylene-6-azacytidine (8) have been synthesized via a multi-step procedure from 6-azauridine. 2'-Deoxy-2'-methylene-5-azacytidine (14a) and 2'-deoxy-2'-methylene-3-deazaguanosine (19a) and their corresponding alpha-anomers (14b and 19b) have been synthesized by the transglycosylation of 3',5'-O-(1,1,3,3- tetraisopropyldisiloxane-1,3-diyl)-2'-deoxy-2'-methyleneu ridine (12) with silylated 5-azacytosine and silylated N2-palmitoyl-3-deazaguanine, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by separation of the isomers and deprotection of the blocking groups. These compounds were tested for cytotoxicity against B16F10, L1210, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1, HSV-1, and HSV-2.

Animals↗
PubMed2006

Synthesis and radiosynthesis of [(18)F]FPhEP, a novel alpha(4)beta(2)-selective, epibatidine-based antagonist for PET imaging of nicotinic acetylcholine receptors.

FPhEP (1, (+/-)-2-exo-(2'-fluoro-3'-phenyl-pyridin-5'-yl)-7-azabicyclo[2.2.1]heptane) belongs to a recently described novel series of 3'-phenyl analogues of epibatidine, which not only possess subnanomolar affinity and high selectivity for brain alpha4beta2 neuronal nicotinic acetylcholine receptors (nAChRs), but also were reported as functional antagonists of low toxicity (up to 15 mg/kg in mice). FPhEP (1, K(i) of 0.24 nM against [(3)H]epibatidine) as reference as well as the corresponding N-Boc-protected chloro- and bromo derivatives (3a,b) as precursors for labelling with fluorine-18 were synthesized in eight and nine steps, respectively, from commercially available N-Boc-pyrrole (overall yields=17% for 1, 9% for 3a and 8% for 3b). FPhEP (1) was labelled with fluorine-18 using the following two-step radiochemical process: (1) no-carrier-added nucleophilic heteroaromatic ortho-radiofluorination from the corresponding N-Boc-protected chloro- or bromo derivatives (3 a,b-1mg) and the activated K[(18)F]F-Kryptofix(222) complex in DMSO using microwave activation at 250 W for 1.5 min, followed by (2) quantitative TFA-induced removal of the N-Boc-protective group. Radiochemically pure (>99%) [(18)F]FPhEP ([(18)F]-1, 2.22-3.33 GBq, 66-137 GBq/micromol) was obtained after semi-preparative HPLC (Symmetry C18, eluent aq 0.05 M NaH(2)PO(4)/CH(3)CN, 80:20 (v:v)) in 75-80 min starting from a 18.5 GBq aliquot of a cyclotron-produced [(18)F]fluoride production batch (10-20% nondecay-corrected overall yield). In vitro binding studies on rat whole-brain membranes demonstrated a subnanomolar affinity (K(D) 660 pM) of [(18)F]FPhEP ([(18)F]-1) for nAChRs. In vitro autoradiographic studies also showed a good contrast between nAChR-rich and -poor regions with a low non-specific binding. Comparison of in vivo Positron Emission Tomography (PET) kinetics of [(18)F]FPhEP ([(18)F]-1) and [(18)F]F-A-85380 in baboons demonstrated faster brain kinetics of the former compound (with a peak uptake at 20 min post injection only). Taken together, the preliminary data obtained confirm that [(18)F]FPhEP ([(18)F]-1) has potential for in vivo imaging nAChRs in the brain with PET.

Animals↗
PubMed2001

Synthesis and In vitro binding affinities of 1-azabicyclic compounds as muscarinic ligands.

Two series of compounds, 2 and 3, were synthesized and their binding affinities were evaluated for the human recombinant muscarinic M(1) receptor subtype expressed in CHO cells. Comparing their binding affinities for the NMS binding sites and the Oxo-M binding sites, they were assumed as agonists. In particular, compound 2e was a good ligand for the agonist binding sites with an IC(50) of 23 nM, which represents over 1585 times stronger binding than for the antagonist binding sites.

Animals↗
PubMed2000

Synthesis and biological evaluation of 1,3-oxathiolane 5-azapyrimidine, 6-azapyrimidine, and fluorosubstituted 3-deazapyrimidine nucleosides.

(2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]- 1,2,4-triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2,4-tr iazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,3, 5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]- 1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19-24) have been synthesized by the transglycosylation of (2R,5S)-1-[2-[[(tert-butyldiphenylsilyl) oxy]methyl]-1,3-oxathiolan-5-yl] cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B16F10, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.

Animals↗