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At least 19 recordsLinked to original sources
PubMed1992

Non-prostanoid thromboxane A2 receptor antagonists with a dibenzoxepin ring system. 2.

A series of 11-[2-(1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxep in-2- carboxylic acid derivatives and related compounds were synthesized and found to be potent TXA2/PGH2 receptor antagonists. Each compound synthesized was tested for its ability to displace [3H]U-46619 binding from guinea pig platelet TXA2/PGH2 receptors. Structure-activity relationship studies revealed that the following key elements were required for enhanced activities: (1) an (E)-2-(1-benzimidazolyl)ethylidene side chain in the 11-position of the dibenzoxepin ring system and (2) a carboxyl group in the 2-position of the dibenzoxepin ring system. The studies also indicated that the TXA2/PGH2 receptor binding affinities of this series of compounds in guinea pig platelet were poorly correlated with those in human platelet. Introduction of substituent(s) to the benzimidazole moiety was effective and sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]- 6,11-dihydrodibenz[b,e]oxepin-2-carboxylate monohydrate (57) recorded the highest affinity for human platelet TXA2/PGH2 receptor with a K(i) value of 1.2 +/- 0.14 nM. It demonstrated potent inhibitory effects on U-46619-induced guinea pig platelet aggregation (in vitro and ex vivo) and human platelet aggregation (in vitro). Compound 57, now designated as KW-3635, is a novel, orally active, and specific TXA2/PGH2 receptor antagonist with neither TXA2/PGH2 receptor agonistic nor TXA2 synthase inhibitory effects. It is now under clinical evaluation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Characterization of thromboxane A2/prostaglandin H2 receptors in porcine coronary artery--the inhibitory effect of a novel dibenzoxepin derivative, KW-3635.

We characterized the thromboxane A2/prostaglandin H2 receptors in porcine coronary artery. The binding of [3H]SQ 29,548, a thromboxane A2 antagonist, to coronary arterial membranes was saturable and displaceable. Scatchard analysis of equilibrium binding showed a single class of high affinity binding sites with a dissociation constant of 18.5 +/- 1.0 nM and the maximum binding of 80.7 +/- 5.2 fmol/mg protein. [3H]SQ 29,548 binding was concentration-dependently inhibited by thromboxane A2 antagonists such as SQ 29,548, BM13505 and BM13177 or the thromboxane A2 agonists such as U46619 and U44069. KW-3635, a novel dibenzoxepin derivative, concentration-dependently inhibited the [3H]SQ 29,548 binding to thromboxane A2/prostaglandin H2 receptors in coronary artery with an inhibition constant of 6.0 +/- 0.69 nM (mean +/- S.E.M.).

Animals↗
PubMed1993

Dibenzoxepin derivatives: thromboxane A2 synthase inhibition and thromboxane A2 receptor antagonism combined in one molecule.

A new series of 6,11-dihydrodibenz[b,e]oxepin derivatives exerting both thromboxane synthase inhibitory (TXS-I) and thromboxane receptor antagonist (TXRA) activities is described. (-)-11-[(3-Pyridylmethyl)thio]-6,11-dihydrodibenz[b,e]oxepin -2- carboxylic acid [(-)-3] and (E)-11-[2-(3-pyridyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin+ ++-2- carboxylic acid methanesulfonate (11E) exhibited potent inhibitory effects on bovine platelet thromboxane synthase with IC50 values of 4.0 and 14 nM, respectively, and these derivatives also antagonized guinea pig platelet TXA2/PGH2 receptors with Ki values of 85 and 180 nM, respectively. Compound 11E exhibited the dual inhibitory activity in ex vivo experiments and demonstrated a significant protective effect in a rat acute renal failure model.

Acute Kidney Injury↗
PubMed1993

Enzymatic optical resolution of dibenzoxepins and its application to an optically active antiallergic agent with thromboxane A2 receptor antagonistic activity.

Methyl (+/-)-11-(2-hydroxyethyl)thio-6,11-dihydrodibenz[b,e]oxepin- 2- carboxylate (5) was enantio-selectively acylated with acetic anhydride in an organic medium by Lipase Amano P to give methyl (-)-11-(2-acetoxyethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2- carboxylate (8), and the (+)-enantiomer by Lipase Sigma Type VII. Using Lipase Amano P, (+)- and (-)-(5) could be prepared with high optical purity (84-94% e.e.). These products were respectively converted to (+)- and (-)-KW-4099, which had antiallergic activity with complete retention of the optical purity.

Acylation↗
PubMed1992

Non-prostanoid thromboxane A2 receptor antagonists with a dibenzoxepin ring system. 1.

A series of 11-[[2-[(arylsulfonyl)amino]ethyl]thio]-6,11- dihydrodibenz[b,e]oxepin-2-carboxylic acids and related derivatives were synthesized. The compounds were tested for their antagonizing effects on guinea pig platelet TXA2/PGH2 receptors. Structure-activity relationships are discussed. (+/-)-11-[[2-[(Styrylsulfonyl)amino]ethyl]-thio]-6,11- dihydrodibenz[b,e]oxepin-2-carboxylic acid (41) and (+/-)-11-[[2-[(phenylsulfonyl)amino]ethyl]thio]-6,11- dihydrodibenz[b,e]thiepin-2-carboxylic acid (4af) were the most promising compounds with K(i) values of 6.5 +/- 0.29 and 3.7 +/- 0.31 nM, respectively, for the TXA2/PGH2 receptor. These compounds also significantly inhibited U-46619-induced guinea pig platelet aggregation ex vivo (10 mg/kg po). Compound 41 was resolved into its optically active form. The (-)-isomer was 60-fold more potent than the (+)-isomer in the TXA2/PGH2 receptor binding assay. Some compounds tested in this study showed both TXA2/PGH2 receptor antagonizing and TXA2 synthase inhibitory effects.

Animals↗
PubMed1992

Effects of KW-3635, a novel dibenzoxepin derivative of a selective thromboxane A2 antagonist, on human, guinea pig and rat platelets.

We examined the binding of [3H]U-46619, a thromboxane A2 agonist, to human and guinea pig platelets and the binding of [3H]SQ 29,548, a thromboxane A2 antagonist, to human, rat and guinea pig platelets. KW-3635 (sodium (E)-11-[2-(5,6-dimethyl-1- benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-c arboxylate monohydrate) concentration-dependently inhibited the [3H]U-46619 binding to human and guinea pig platelets with inhibition constants of 1.2 nM and 2.7 nM, respectively. KW-3635 also potently inhibited the [3H]SQ 29,548 binding to human and guinea pig platelets with inhibition constants of 1.9 nM and 3.2 nM, respectively. In contrast, KW-3635 was less active against thromboxane A2/prostaglandin H2 receptors in rat platelets with an inhibition constant of 97 nM. KW-3635 at 10(-5) M did not antagonize various receptors including prostaglandin E2, prostaglandin I2 and neurotransmitters. In addition, 10(-5) M KW-3635 did not alter the prostaglandin D2-induced cAMP accumulation in EBTr cells. KW-3635 was inactive towards thromboxane synthase, cyclooxygenase and prostaglandin I2 synthase up to 10(-5) M. KW-3635 slightly inhibited 5-lipoxygenase with an IC50 value of 71 microM. These data indicate that KW-3635 is a potent and selective non-prostanoic thromboxane A2 antagonist, and it can recognize the species differences in thromboxane A2/prostaglandin H2 receptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Synthesis and antiallergic activity of 11-(aminoalkylidene)-6,11-dihydrodibenz[b,e]oxepin derivatives.

A new series of 11-substituted 6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid derivatives was synthesized and demonstrated to be orally active antiallergic agents. These compounds are structurally related to 1 (KW-4994), which we had reported previously to be a new antiallergic agent. Most compounds synthesized exhibited potent inhibitory effects on 48-h homologous passive cutaneous anaphylaxis (PCA) in rats and on IgG1-mediated bronchoconstriction in guinea pigs. Additionally, compounds possessing a terminal carboxyl group at the 2-position of the dibenz[b,e]oxepin ring system exhibited inhibitory effects on specific [3H]pyrilamine binding to guinea pig cerebellum histamine H1 receptors, whereas these demonstrated negligible effects on specific [3H]QNB binding to rat striatum muscarinic acetylcholine M1 receptors. Structure-activity relationship studies revealed that the following key elements were required for enhanced antiallergic activities: (1) a 3-(dimethylamino)propylidene group as the side chain at the 11-position, (2) a terminal carboxyl moiety at the 2-position, and (3) a dibenzoxepin ring system. Among the compounds synthesized, (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride (16) was selected for further evaluation. It had an ED50 value of 0.049 mg/kg po in the PCA test in rats and an ID50 value of 0.030 mg/kg po in inhibiting anaphylactic bronchoconstriction in guinea pigs. Furthermore, it had a Ki value of 16 +/- 0.35 nM for the histamine H1 receptor, while it exhibited negligible CNS side effects up to a dose of 600 mg/kg po. Compound 16 is now under clinical evaluation as KW-4679.

Animals↗
PubMed1978

Nonsteroidal antiinflammatory agents. 2. Derivatives/analogues of dibenz[b,e]oxepin-3-acetic acid.

6,11-Dhydro-11-oxodibenz[b,e]oxepins and some related compounds have been synthesized and evaluated for antiinflammatory effect according to the carrageenan paw edema method in rats. The structure-activity relationships have been discussed among acetic acid, carboxylic acid, alcohol, and tetrazole derivatives of dibenzoxepins and acetic acid derivatives of thienobenzoxepins and of the corresponding thiepins. The 3-isopropyl alcohol 9 and 11-deoxo-3-propionic acid (49) were more active than indomethacin but not as active as the title compound (i.e., 43). Carboxylic acids, tetrazoles, esters, amides, and ketones were less active than the corresponding acetic acids. Three compounds (31, 33, and 34) were evaluated for ulcerogenicity and lethality but none surpassed 6,11-dihydro-11-oxodibenz[b,e]oxepin-3-acetic acid (41) in therapeutic ratio.

Animals↗
PubMed1996

Dibenzoxepinone hydroxylamines and hydroxamic acids: dual inhibitors of cyclooxygenase and 5-lipoxygenase with potent topical antiinflammatory activity.

Hydroxylamine and hydroxamic acid derivatives of a known nonsteroidal antiinflammatory dibenzoxepine series display both cyclooxygenase (CO) and 5-lipoxygenase (5-LO) inhibitory properties. Many of these new dual CO/5-LO inhibitors also exhibit potent topical antiinflammatory activity in the arachidonic acid-induced murine ear edema model. On the basis of their promising profile of in vitro and in vivo activities, hydroxamic acids 24h, 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-++ +methylpropanamide (HP 977), and 25, 3-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-hydroxy-N- methylpropanamide (P10294), were selected as developmental candidates for the topical treatment of inflammatory skin disorders.

3T3 Cells↗
PubMed1982

Haemodynamic effects of BM 10.188, a new orally active inotropic agent, in healthy volunteers.

1 BM 10.188 (Doxaminol, Boehringer Mannheim, GmbH) is a recently developed beta-sympathomimetic agent which has shown promising positive inotropic activity in experimental animal models. It is a dibenzoxepine derivative. 2 The effects of 20 mg oral BM 10.188 on systolic time intervals and standard echocardiographic parameters have been studied in six normal healthy male volunteers. 3 When assessed by repeated measured analysis of variance, QS2 and LVET shortened significantly (P less than 0.005) in the 8 h period following BM 10.188. Mean maximum shortening values were: QS2, 25.7 +/- 25.6 (s.d.) ms at 155 min and LVET, 10.7 +/- 9.5 (s.d.) ms at 155 min. There was a corresponding small but significant increase of 4.2 +/- 3.9 (s.d.) ml in stroke volume at 6 h (P less than 0.025). 4 These results indicate that in normal volunteers, BM 10.188 exhibits effects on noninvasive cardiological indices similar to those observed after cardiac glycosides.

Adolescent↗
PubMed1978

[Induction of hepatic tyrosine transaminase in rats by phenothiazine derivatives and analogs].

We have showed induction of tyrosine-alpha-ketoglutarate transaminase in hepatic cytosol of Rats (Wistar strain) five hours after intraperitoneal administration of tricyclic compounds (phenothiazine, iminodibenzyl, thioxanthene, thiophenylpyridylamin, dibenzocycloheptadiene, dibenzoxepin derivatives). Chemical structure of these molecules is very important: sulfur atom (phenothiazine, thioxanthene), some substituants like chlorine (chlorpromazine, chlorprothixene) and 2'-dimethylaminopropyl chain (promethazine) increase this inductive effect.

Animals↗
PubMed1986

Antiinflammatory and aldose reductase inhibitory activity of some tricyclic arylacetic acids.

A number of dibenztropone, dibenzsuberone, dibenzoxepin, and dibenzthiepin acetic acids were synthesized and tested for antiinflammatory/analgesic activity and also for their ability to inhibit rabbit lens aldose reductase (AR). It was found that the structural requirements for antiinflammatory/analgesic activity, believed to be mediated by inhibition of cyclooxygenase, were much more stringent than were those for AR inhibition. For example, the introduction of a hydroxyl group into positions 1, 4, 6, 7, or 8 on dibenzsuberone-2-acetic acid (1a) had relatively little effect on AR inhibition, but caused wide variations in antiinflammatory/analgesic activity.

Acetates↗
PubMed1983

Tricyclic triarylethylene antiestrogens: dibenz[b,f]oxepins, dibenzo[b,f]thiepins, dibenzo[a,e]cyclooctenes, and dibenzo[b,f]thiocins.

The bridging groups O, S, CH2CH2, and SCH2 were used to produce a series of 26 tricyclic triarylethylenes. Their in vitro binding to rat uterine estrogen receptor was measured in a competitive binding assay. Antifertility and uterotrophic tests in rats showed that antiestrogenic activity was present. The most interesting series had a basic side chain, and the most potent compounds were 3-[2-(dimethylamino)ethoxy] -10-ethyl-11-(4-hydroxyphenyl)dibenzo[b,f]thiepin (7b) and 3-[2-(dimethylamino)ethoxy]-11-ethyl-12-(4-hydroxyphenyl)-5,6-dihydrodibenzo[a,e]-cyclooctene (7c), which had good binding (approximately 50% relative to estradiol) and good antiestrogenic activity (ca. one-half of the potency of tamoxifen, III). In this series, the O-bridged compound was the least active, and this is interpreted in terms of the flatness of the dibenzoxepin ring system. Sedative activity was found in some of the compounds.

Animals↗
PubMed1991

Pharmaco-EEG profile of maroxepine: third example to discuss the predictive value of pharmaco-electroencephalography in early human pharmacological evaluations of psychoactive drugs.

This publication forms the third part of a critical evaluation of pharmaco-EEG applications as an instrument for assessing the profile of action of psychoactive drugs based on the trial results of three new psychoactive test substances: savoxepine, levoprotiline and maroxepine. After the presentation, in Parts I (savoxepine) and II (levoprotiline), of trial substances for which compatible results were obtained in the pharmaco-EEG model and in the clinical studies, a case with discrepant and less predictive results has been presented, and on this basis the limitations of the pharmaco-EEG model in the evaluation of therapeutic efficacy are discussed. The substance examined in this report, the tetracyclic dibenzoxepine derivative, maroxepine, produced prominent central effects in pharmacological studies which pointed to a bipolar profile of action, i.e., the EEG showed similarities both to antidepressants and antipsychotics. The pharmaco-EEG effects of maroxepine were investigated in a randomised, double-blind study in 15 young healthy male subjects and compared with those of placebo and the reference substances, chlorpromazine and imipramine. The experimental design was a cross-over uncompleted block design with five consecutive trial days one week apart. The pharmaco-EEG was recorded from the occipito-temporal and frontocentral regions before, 3 and 6 h after application of 2.5 mg and 5.0 mg maroxepine, 75 mg chlorpromazine, 75 mg imipramine and placebo. The selected target variables for descriptive statistical evaluation were the Spectral Difference Index (SDI), the absolute and relative power values in seven predetermined frequency bands within the range 1.5 to 30.0 Hz, the dominant frequency (6.0 to 18.0 Hz) and the alpha slow-wave index (ASI). The results show that maroxepine has a potent central nervous action and a strong sedative potential. The EEG effects consisted of a shift to the left of the relative power spectrum of the occipital lead, accompanied by an increase in the absolute beta power in the frontocentral region. Discriminative inspection of the profiles of EEG changes, induced by maroxepine and the reference drugs, revealed closer similarity of maroxepine with chlorpromazine than with imipramine. Maroxepine showed vigilance-decreasing features like imipramine. This is one condition to be able to interfere with depressive illness. The underlying hypothesis is that depressive illness is based on affective and vigilance disturbance. Maroxepine furthermore showed the typical neuroleptic-like shift from resting alpha to resting subalpha (theta F band) which we assume related to the anti-productive properties of neuroleptics in schizophrenia.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗