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Biomedical subjects

J H Fleisch

Publications and source records attributed to J H Fleisch.

At least 37 records · Page 2Linked to original sources
PubMed1992

Optimization of the quinoline and substituted benzyl moieties of a series of phenyltetrazole leukotriene D4 receptor antagonists.

This report describes the development of a series of highly potent quinoline-based leukotriene D4 (LTD4) receptor antagonists containing an N-benzyl-substituted phenyltetrazole moiety. They were designed to provide both the correct positioning of the acidic function and secondary lipophilic domain required for strong receptor binding. Members of this series possess high activity in blocking LTD4-induced contractions of isolated guinea pig ileum. Compound 32, LY287192 (2-[[5-[3-[2-(7-chloroquinolin-2- yl)ethenyl]phenyl]-2H-tetrazol-2-yl]methyl]-5-fluorobenzoic acid sodium salt), blocked contraction with a pKB value of 9.1 +/- 0.3. Qualitative structure-activity studies have demonstrated specific requirements for the best activity. In particular, ortho substitution of the benzyl group with an acidic function was crucial for maximum potency. In cases similar to 32, where the benzyl group possesses an ortho carboxylate, the N-2-substituted tetrazole isomer showed 100-fold greater activity relative to the corresponding N-1 isomer. This pattern was reversed when the acid was substituted at the para position. The quinoline unit may be replaced by other nitrogen-containing heterocycles.

Animals↗
PubMed1992

Pharmacological and histological examinations of regional differences of guinea-pig lung: a role of pleural surface smooth muscle in lung strip contraction.

1. Parenchymal lung strip preparations have been widely used as an in vitro model of peripheral airway smooth muscle. The present study examined functional responses of 4 consecutive guinea-pig lung parenchymal strips isolated from the central region (segment 1) to the distal edge (segment 4) of the lower lung lobe. The middle two segments were designated as segments 2 and 3. 2. Lung segments 1 and 4 exhibited significantly greater contraction than the other 2 segments to KCl when responses were expressed as mg force per mg tissue weight. Contractile responses to bronchospastic agents including histamine, carbachol, endothelin-1, leukotrienes (LT) B4 and D4, and the thromboxane A2-mimetic U46619 demonstrated no significant difference in EC50 values among the 4 lung segments. 3. Contractile responses of segments 1 and 4 to antigen-challenge (ovalbumin), ionophore A23187 and substance P were significantly greater than the other 2 segments with respect to either sensitivity or maximum responsiveness. 4. U46619-induced contractions of the 4 lung segments were relaxed in similar manner by papaverine and theophylline up to 100%, salbutamol up to 80%, and sodium nitroprusside by only 20%. In contrast, sodium nitroprusside markedly reversed U46619-induced contraction of pulmonary arterial rings and bronchial rings. 5. Histological studies identified 2-4 layers of smooth muscle cells underlying the lung pleural surface. Mast cells were prominent in this area. Moreover, morphometric studies showed that segment 4 possessed the least amount of smooth muscle structures from bronchial/bronchiolar wall and vasculatures as compared to the other 3 segments, and a significant difference in this respect was evident between segment 1 and segment 4.6. Since lung segments 1 and 4 are covered with larger surface area of lung pleura, the present results suggest that the significantly greater intrinsic contractile responses of segments 1 and 4 are associated with the presence of increased lung pleural surface possibly together with more mast cells. Thus, a primary contribution to the net contraction of the lung parenchymal strips may be smooth muscle from the lung pleura, alveolar ducts and interstitial contractile cells rather than from bronchi/bronchioles and microvasculatures.

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

Pharmacologic evaluation of A23187-induced contractions of three distinct preparations of guinea pig lung parenchymal strips.

The present investigation examined the pharmacologic profiles of three distinct guinea pig lung parenchymal strips (LPS): intact LPS, denuded LPS (devoid of any lung pleura) and pleural surface strips. All three preparations responded similarly to increasing concentrations of KCl, whereas maximum contractile responses of the intact LPS and pleural surface strips to histamine, LTD4 and U46619, a thromboxane A2 mimetic, were significantly greater (P less than 0.001) than those elicited by the denuded LPS. Moreover, concentration-response curves for intact LPS and pleural surface strips to ovalbumin and ionophore A23187 challenges were equivalent to each other, which were significantly (P less than 0.001) higher in magnitude than that for the denuded LPS. The net contractile response of the denuded LPS to A23187 was significantly reduced by 35% in the presence of 1 x 10(-5) M A-64077, a 5-lipoxygenase inhibitor, and nearly abolished with the addition of 1 x 10(-6) M pyrilamine and 4 x 10(-6) M indomethacin. In contrast, the maximum contractile responses of the intact LPS and pleural surface strips were reduced by 40 and 30%, respectively, in the presence of all three inhibitors. On the other hand, morphometric analysis revealed that the density of mast cells in the smooth muscle of lung pleura was as high as that found in the bronchiolar area (2.35 +/- 0.31 vs. 2.62 +/- 0.28 per 0.05 mm2). In contrast, mast cells were scarcely identified in the alveolar parenchyma.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

(Phenylmethoxy)phenyl derivatives of omega-oxo- and omega-tetrazolylalkanoic acids and related tetrazoles. Synthesis and evaluation as leukotriene D4 receptor antagonists.

Two series of (phenylmethoxy)phenyl compounds derived from the structure of LY163443 were synthesized and evaluated as leukotriene D4 receptor antagonists. In the omega-[(phenylmethoxy)phenyl]-omega-oxoalkanoic acid series, 5-[4-[(4-acetyl-2-ethyl-3-hydroxyphenyl)methoxy]phenyl]-3,3-dimethyl-5- oxopentanoic acid (8) was the most potent antagonist of LTD4-induced contractions of guinea pig ileum (pKB of 7.60) and LTD4 pressor response in pithed rats (ED50 of 1.4 mg/kg iv). Replacing the carboxylic acid function with 5-tetrazole gave slightly more potent compounds. In the omega-[5-[[(phenylmethoxy)phenyl]alkyl] tetrazolyl]alkanoic acid series, replacing the carboxylic acid with 5-tetrazole gave compounds that were equally effective in the guinea pig ileum but more potent in vivo against the LTD4 pressor response in rat. The pKB value in the guinea pig ileum for 1-[2-hydroxy-3-propyl-4- [[4-[[2-[3-(1H-tetrazol-5-yl)propyl]-2H-tetrazol-5-yl]methyl ] phenoxy]methyl]phenyl]ethanone (25) was 7.87 and the ED50 for antagonism of the LTD4 pressor response was 4.0 mg/kg iv. The sodium salts of 8 (9) and 25 (26) given by the iv route of administration antagonized LTD4-induced cardiovascular alterations in anesthetized rat and LTD4-induced bronchoconstriction in guinea pig in a dose-dependent manner. Oral activity was also demonstrated against the LTD4-induced bronchoconstriction in guinea pig.

Acetophenones↗
PubMed1990

Leukotriene receptor antagonism and augmentation of beta-receptor-mediated events by LY171883.

LY171883, (1-[2-hydroxy-3-propyl-4-[4(1H-tetrazol-5-yl)butoxy)phenyl]etha none), a leukotriene (LT) D4/E4 receptor antagonist, was assessed in comparison with two well known phosphodiesterase inhibitors, isobutylmethyl-xanthine (IBMX) and theophylline, for its ability to augment beta-receptor-mediated responses. Relaxation of carbachol-contracted guinea-pig trachea by isoprenaline was enhanced by the three agents in a dose-dependent manner. A two-fold enhancement of isoprenaline-induced smooth muscle relaxation was produced by 2.5 microM IBMX, 28 microM LY171883, or 140 microM theophylline. Similar concentrations of IBMX or theophylline did not antagonize LTE4-induced tracheal contractions; LY171883 totally inhibited the response and had significant LTE4 receptor antagonist activity even at 10-fold lower concentrations. Antigen-induced release of histamine and LTC4 from guinea-pig lung was reduced by isoprenaline. Prior treatment with LY171883, IBMX, or theophylline did not enhance this action. Isoprenaline reduced histamine-induced bronchospasm in anaesthetized guinea-pigs. LY171883, 30 mg kg-1, or IBMX, 1 mg kg-1, did not affect the isoprenaline-induced decrease in the histamine response. IBMX, 3 mg kg-1, and theophylline, 30 mg kg-1, augmented the isoprenaline-induced bronchodilation. LTE4-induced bronchoconstriction was not affected by IBMX or theophylline whereas LY171883 antagonized this response at doses as low as 3 mg kg-1. Therefore, in both in-vitro and in-vivo test systems, LY171883 functioned primarily as a leukotriene receptor antagonist with minimal pharmacological activity attributable to its ability to potentiate isoprenaline.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Leukotriene (LT) receptor antagonists. Heterocycle-linked tetrazoles and carboxylic acids. LY203647.

LY171883, 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl] ethanone, is an orally active antagonist of LTD4- and LTE4-induced responses in a variety of test systems. We prepared a new series of LT antagonists based on a proposed model of LY171883 binding to the LTE4 receptor in which the n-propyl and tetrazole moieties of LY171883 occupy those parts of the receptor to which the C1-C5 chain and the cysteinyl carboxyl of LTE4 bind, respectively. The new compounds have an acidic function corresponding to the glycine carboxyl of LTD4 linked through a heterocyclic group which is proposed to bind to the LTD4 receptor where the cysteinyl glycine amide bond of LTD4 binds. LY203647, 1-[2-hydroxy-3-propyl-4-[4-[2-[4-(1H-tetrazol-5-yl)butyl]-2H- tetrazol-5-yl]butoxy]phenyl] ethanone, showed good LTD4 antagonist activity with a suitable pharmacologic and toxicologic profile and has been chosen for clinical evaluation.

Acetophenones↗
PubMed1988

Serotonin-induced pulmonary responses in the perfused guinea pig lung: evidence for 5HT2 receptor-mediated pulmonary vascular and airway smooth muscle constriction.

The isolated perfused guinea pig lung was used to investigate pharmacologic characteristics of serotonin receptors in pulmonary vascular and airway smooth muscle. Serotonin caused a marked dose-related increase in pulmonary arterial pressure and peak intratracheal pressure when injected into the pulmonary artery. In contrast to serotonin, 5-carboxamidotryptamine, a 5HT1A and 5HT1B receptor agonist, and 2-methylserotonin, a 5HT3 receptor agonist produced only weak vascular and airway responses. Furthermore, vasoconstriction and bronchoconstriction elicited by serotonin were antagonized by the potent 5HT2 receptor antagonists, LY53857, ketanserin, and ritanserin. Antagonist specificity for 5HT2 receptors was demonstrated in the perfused guinea pig lung since similar responses induced by histamine were not blocked. High concentrations of serotonin were tachyphylactic on vascular but not airway constriction. Tachyphylaxis of vascular responses was not observed to an equipotent concentration of leukotriene D4 (LTD4). Thus, both the pulmonary vascular and airway constriction to serotonin were predominantly due to 5HT2 receptor activation. Furthermore, tachyphylaxis of vascular responses to serotonin might prove useful to differentiate 5HT receptor systems in pulmonary blood vessels from those in airways.

Animals↗
PubMed1988

Leukotriene receptor antagonists. 4. Synthesis and leukotriene D4/E4 receptor antagonist activity of 4-(alkyl)acetophenone derivatives.

Analogues of the leukotriene D4/E4 receptor antagonist LY171883 (1a) were synthesized in which the tetrazole was linked to the hydroxyacetophenone moiety by an all-methylene carbon chain. A key step in the synthesis involved a Wittig olefin-forming reaction between 3-methoxy-2-propylbenzaldehyde and the ylide derived from (4-carboxybutyl)triphenylphosphonium bromide to form the desired carbon chain. A regioselective Fries rearrangement was employed to form the o-hydroxyacetophenone. Compounds in which the tetrazole was separated from the acetophenone by four and five methylene groups were compared to the corresponding derivatives in which an oxygen atom linked the tetrazole chain to the aromatic ring for their ability to antagonize LTD4- or LTE4-induced contractions of the isolated guinea pig ileum. When compared to 1a, the "carba" analogue, 7a, showed nearly identical LTD4 antagonist activity. The LTE4 antagonist activity for these two compounds was also identical. In the shorter chain series, the "carba" analogue, 7b, showed enhanced LTD4 antagonist activity and approximately 10-fold greater LTE4 antagonist activity. These results suggest that the oxygen atom para to the acetyl group of 1a and 1b is not of major importance for association with the LTD4 or LTE4 receptor sites in the guinea pig ileum.

Acetophenones↗
PubMed1988

Antigen-induced edema formation, bronchoconstriction, and pulmonary vasospasm in the isolated perfused guinea pig lung. Evidence for a secondary edemagenic response.

The effect of antigen (ovalbumin) challenge on pulmonary hemodynamics, bronchoconstriction, and fluid filtration was investigated in Ringer's-perfused (non-recirculating) lungs that had been passively sensitized in vitro. Bolus ovalbumin injection (30 micrograms) produced immediate increases in pulmonary arterial pressure, peak intratracheal pressure, and lung weight within 1 min and secondary marked increases in intratracheal pressure and lung weight from 120 to 200 min. Electron microscopy of antigen-challenged isolated lungs showed evidence of both septal and intraalveolar edema. Ionophore A23187 (100 micrograms) challenge of nonsensitized lungs produced immediate pulmonary responses similar to antigen, whereas secondary increases in lung weight were smaller. Arachidonic acid pretreatment (1 microM) potentiated immediate antigen-induced increases in intratracheal pressure but did not affect pulmonary responses to ionophore challenge. Putative mediators of anaphylaxis including histamine, leukotrienes B4, C4, D4, and E4, platelet-activating factor, and substance P produced immediate changes in pulmonary arterial and/or intratracheal pressure similar to antigen challenge. Only platelet-activating factor and substance P partially mimicked the secondary edema formation noted following antigen challenge. Thus, antigen challenge in in vitro sensitized guinea pig lungs produced both immediate and secondary responses characterized by increases in vascular pressure, airway pressure, and edema formation. This occurred in the absence of circulating blood-formed elements and without a massive influx of cells. Synergism between mediators such as histamine, the leukotrienes, platelet-activating factor, and substance P released following antigen challenge may be necessary to produce the complete pathophysiological sequelae associated with antigen challenge in the perfused guinea pig lung.

Anaphylaxis↗
PubMed1988

Leukotriene receptor antagonists. III. Pharmacological and chemical studies with LY137617, a leukotriene D4 and leukotriene E4 receptor antagonist.

A series of chlorophenoxyalkyl acids were prepared and evaluated as pharmacological antagonists of leukotriene D4. Structure-activity relationship studies pointed to LY137617 as a compound with possible therapeutic value. In experiments on isolated smooth muscles from the guinea-pig, this agent was a selective and moderately potent antagonist of leukotriene D4 and also leukotriene E4. Other in vitro experiments demonstrated that LY137617 had a high affinity for protein molecules. This was reflected in vivo as a weaker than expected efficacy against leukotriene-mediated events, limiting the compound's potential as a clinical candidate. Nevertheless, agents of this type will prove useful in the laboratory to increase knowledge of leukotriene receptor-antagonist interactions.

Animals↗
PubMed1987

Pharmacologic analysis of LY188695 (KB-2413), 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-benzimidazole difumarate, a potent histamine1 receptor antagonist.

LY188695 was evaluated both in vitro and in vivo in the guinea pig to determine its pharmacologic profile. The compound antagonized histamine-induced contractions of ileum, aorta, and trachea with pKB values of 9.9, 9.9, and 9.2 respectively. In the lung parenchymal strip, LY188695 caused a rightward shift of the histamine concentration-response curve with a reduction in the maximal response at all antagonist concentrations tested. The reason for this effect is unknown, but it was not due to a nonspecific depressant action of the compound on the parenchyma. Selectivity was shown by its inactivity against leukotriene D4, bradykinin, prostaglandin F2 alpha, acetylcholine, norepinephrine, and serotonin on various guinea pig and rat smooth muscles. Similarly, H2 receptor-mediated relaxation of the rat uterus was unaltered by LY188695. Increases in total pulmonary impedance caused by i.v. histamine to anesthetized guinea pigs were reduced by as little as 3 micrograms/kg given orally 1 hour prior to histamine challenge. In this system, LY188695 was 15 times more potent than chlorpheniramine and 100 times more potent than terfenadine. Similar responses elicited by acetylcholine were not antagonized by LY188695. A duration of action greater than 4 hours was observed in this model. Ovalbumin given i.v. to sensitized guinea pigs increased total pulmonary impedance which was markedly decreased after oral administration of 30 or 100 micrograms/kg LY188695. These results indicate that LY188695 is a very potent antagonist of H1-mediated responses and suggest that this agent might be useful in disease states characterized by an overproduction of histamine.

Animals↗
PubMed1987

Structure-activity relationships (SAR) of the 3-alkyl substituents among a series of hydroxy-acetophenone leukotriene antagonists.

LY171883 is an orally active antagonist of leukotriene (LT) D4 and LTE4. A series of related compounds varying the position and nature of the alkyl side chain were synthesized and evaluated for their ability to block LTD4-induced contraction of guinea pig ileum. Maximal activity was obtained with n-propyl, n-butyl, and n-pentyl substituents with slightly reduced activity for longer side chains. Polar groups on the side chain substantially reduced activity. Thus, it appears that the leukotriene receptor site requires a nonpolar alkyl group of moderate size at the 3-position on this type of receptor antagonist.

Acetophenones↗
PubMed1987

Leukotriene receptor antagonists. 1. Synthesis and structure-activity relationships of alkoxyacetophenone derivatives.

A series of derivatives of 2,4-dihydroxy-3-propylacetophenone(1) were prepared and examined for their ability to block leukotriene D4 (LTD4) induced contraction of guinea pig ileum. Straight-chain carboxylic acids where the carboxyl group was separated from the acetophenone moiety by varying numbers of methylenes were evaluated, and maximum activity was obtained with the pentamethylene acid (6). Examination of ring substitution showed that the 2-propyl-3-hydroxy-4-acetyl substitution pattern was required for maximum LTD4 antagonist activity. Additional chain terminal groups were examined, and the acidic 5-tetrazolyl group separated from the acetophenone moiety by four to seven methylenes (26, 23, 27, 28) gave excellent in vitro and in vivo activities. Compound 26 (LY171883) had the best balance of in vitro and in vivo activity. It lacked bronchospastic activity at the doses administered and has been chosen for clinical evaluation.

Acetophenones↗
PubMed1987

Leukotriene receptor antagonists. 2. The [[(tetrazol-5-ylaryl)oxy]methyl]acetophenone derivatives.

A series of [[(tetrazol-5-ylaryl)oxy]methyl]acetophenones was synthesized and evaluated as antagonists of leukotriene D4 induced contractions of guinea pig ileum. Substitutions at the 3-position of the acetophenone with ethyl (66), propyl (68), butyl (83), and isobutyl (84) gave -log IC50 values of 7.9, 8.0, 7.8, and 7.7, respectively. Equally potent compounds were obtained when the tetrazol-5-yl group was connected to the second benzene ring in the para position with a chemical bond (67), methylene (68), or ethylene (71). For retention of high antagonist activity, the acetophenone should be substituted in the 2-position by a hydroxyl group and the tetrazole ring should have an acidic hydrogen atom. 1-[2-Hydroxy-3-propyl-4-[[4-(1H-tetrazol-5-ylmethy) phenoxy]methyl]phenyl]ethanone (68, LY1632443) has undergone extensive pharmacologic evaluation for its potential as an antiasthma agent.

Acetophenones↗
PubMed1986

Evaluation of LY163443, 1-[2-hydroxy-3-propyl-4-([4- (1H-tetrazol-5-ylmethyl)phenoxy]methyl) phenyl]ethanone, as a pharmacologic antagonist of leukotrienes D4 and E4.

LY163443,1-[2-hydroxy-3-propyl-4-([4- (1H-tetrazol-5-ylmethyl)phenoxy]- phenoxy]methyl)phenyl]ethanone, antagonized LTD4-induced contractions of guinea pig ileum, trachea, and lung parenchyma. Tracheal contractions to LTE4 were also inhibited by LY163443. The compound had minimal effect against ileal responses to LTC4 and parenchymal contractions to LTB4. Furthermore, LY163443 had little to no effect against contractions of isolated smooth muscles to histamine, bradykinin, PGF2 alpha, carbachol, serotonin or U46619. LY163443, given by oral administration to guinea pigs, blocked LTD4-induced increases in total pulmonary impedance (TPI). Similar responses elicited by histamine or U46619 were unaffected. Increases in TPI in response to i.v. administration of LTC4 were antagonized by LY163443 given by the same route. Ovalbumin challenge also increased TPI in guinea pigs previously sensitized against this antigen. In such animals, pretreated with pyrilamine, propranolol, and indomethacin, oral administration of LY163443 blocked the increase in TPI caused by ovalbumin. Additionally, LTD4 given intradermally to guinea pigs caused a vascular leakage which was suppressed by prior oral administration of LY163443. Finally, LY163443 relaxed isolated guinea pig trachea previously contracted with LTD4, histamine, or carbachol. Relaxation of tissues contracted by these latter two agonists suggested some inherent airway smooth muscle relaxant properties of the molecule. This was further demonstrated by showing some bronchodilator activity in an in vivo setting. Thus, this pharmacologic profile indicates that LY163443, or a member of the same chemical family, warrants consideration as a possible therapeutic agent in the treatment of asthma and in diseases characterized by an overproduction of LTD4 and LTE4.

Acetophenones↗
PubMed1985

LY83583: an agent that lowers intracellular levels of cyclic guanosine 3',5'-monophosphate.

A novel compound, LY83583 (6-anilino-5,8-quinolinedione), was found to lower basal levels of cyclic GMP (cGMP) in fragments of guinea-pig lung incubated in vitro. The lowering of cGMP was dose-related reaching a maximum of 72% at 5 X 10(-5) M. Basal levels of cyclic AMP (cAMP) were not lowered by LY83583. cGMP concentrations were also reduced in guinea-pig heart and cerebellum after incubation with LY83583. However, the drug did not alter the levels of this cyclic nucleotide in spleen. Exposure of lung fragments from sensitized guinea pigs to ovalbumin resulted in a marked increase in cGMP and cAMP. LY83583 prevented completely the accumulation of cGMP and attenuated the rise in cAMP. Similar results were obtained in rat cerebellum stimulated with kainic acid. The compound also blocked ovalbumin-induced release of slow reacting substance of anaphylaxis (leukotrienes) from guinea-pig lung. Subcutaneous administration of LY83583 to guinea pigs did not affect cGMP concentrations in vivo in lung, but the total amount of cGMP in spleen was reduced dramatically. This was accompanied by a marked splenomegaly. LY83585 did not inhibit lung guanylate cyclase. In fact, activity was increased in a cell-free preparation from guinea-pig lung. The mechanism by which LY83583 reduced concentrations of cGMP is presently unknown. Nevertheless, our studies suggest that LY83583 will be a valuable pharmacological tool to help elucidate the role of cGMP in biological events.

Aminoquinolines↗