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R P Steffen

Publications and source records attributed to R P Steffen.

At least 19 recordsLinked to original sources
PubMed2006

Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases.

Efaproxiral (Efaproxyn, RSR13), a synthetic allosteric modifier of haemoglobin (Hb), decreases Hb-oxygen (O(2)) binding affinity and enhances oxygenation of hypoxic tumours during radiation therapy. This analysis evaluated the Phase 3, Radiation Enhancing Allosteric Compound for Hypoxic Brain Metastases; RT-009 (REACH) study efficacy results in relation to efaproxiral exposure (efaproxiral red blood cell concentration (E-RBC) and number of doses). Recursive partitioning analysis Class I or II patients with brain metastases from solid tumours received standard whole-brain radiation therapy (3 Gy/fraction x 10 days), plus supplemental O(2) (4 l/min), either with efaproxiral (75 or 100 mg/kg daily) or without (control). Efaproxiral red blood cell concentrations were linearly extrapolated to all efaproxiral doses received. Three patient populations were analysed: (1) all eligible, (2) non-small-cell lung cancer (NSCLC) as primary cancer, and (3) breast cancer primary. Efficacy endpoints were survival and response rate. Brain metastases patients achieving sufficient E-RBC (> or =483 microg/ml) and receiving at least seven of 10 efaproxiral doses were most likely to experience survival and response benefits. Patients with breast cancer primary tumours generally achieved the target efaproxiral exposure and therefore gained greater benefit from efaproxiral treatment than NSCLC patients. This analysis defined the efaproxiral concentration-dependence in survival and response rate improvement, and provided a clearer understanding of efaproxiral dosing requirements.

Aniline Compounds↗
PubMed2001

Enhancement of tumor oxygenation and radiation response by the allosteric effector of hemoglobin, RSR13.

Prior studies using pO(2) microelectrodes have shown that RSR13, an allosteric modifier of hemoglobin, increases tissue oxygenation in vivo. Recently, measurements of tissue oxygenation have been performed by many investigators using blood oxygen level-dependent magnetic resonance imaging (BOLD MRI). In this study, we tested the hypothesis that the BOLD MRI signal ratio in tumors will change after administration of RSR13. NCI-H460 human lung carcinoma cells were used as a xenograft in athymic nude mice. Mice with 1-cm(3) tumors in the flank were anesthetized and mounted on the MRI apparatus, and various doses of RSR13 were administered intraperitoneally (i.p.). MR images were then acquired at 10-min intervals for up to 60 min after injection. The effect of RSR13 on tumor response was studied using the same mouse xenograft model with tumor growth delay measurements. RSR13 increased the MRI signal ratio [Intensity(t)/Intensity(t = 0)] in a dose-dependent manner, with maximum increases occurring 30 min after RSR13 was administered. An RSR13 dose of 200 mg/kg proved to be optimum. Since the MRI signal ratio has been shown previously to be linearly related to tissue oxygenation, the changes in the MRI signal ratio can be attributed to changes in tumor oxygen levels. Using a 200-mg/kg dose of RSR13, with a 10-Gy dose of radiation administered to tumors 30 min later, enhancement of radiation-induced tumor growth delay by RSR13 was observed (enhancement factor = 2.8). Thus our MRI results support and verify the previously reported RSR13-induced increase in tumor oxygenation obtained using pO(2) microelectrodes. Based upon these results and other previous studies, the mechanism of enhancement of the effect of radiation by RSR13 probably involves an increase in tumor oxygenation.

Allosteric Regulation↗
PubMed2000

Post-ischemic RSR13 amplifies the effect of dizocilpine on outcome from transient focal cerebral ischemia in the rat.

In a recent study of focal cerebral ischemia in rats, pre-ischemic administration of the synthetic allosteric hemoglobin modifier RSR13 (2-[4-[[3,5-dimethylanilino) carbonyl] methyl] phenoxy]-2-methylproprionic acid) reduced cerebral infarct size when combined with the NMDA receptor antagonist dizocilpine (MK-801) but not when given alone. We hypothesized that post-ischemic RSR13 administration would enhance neuroprotection afforded by NMDA receptor antagonism in a rat model of transient middle cerebral artery occlusion (MCAO). Fasted normothermic Wistar rats underwent 75 min of temporary MCAO. At onset of reperfusion, rats randomly received: (1) 0.9% NaCl (vehicle) i.v. alone (n=16); (2) 0.9% NaCl+dizocilpine (0.25 mg/kg) i.v. (n=16); or (3) RSR13 (150 mg/kg)+dizocilpine (0.25 mg/kg) i.v. (n=17). Seven days later, neurologic deficit and cerebral infarct size were determined. Dizocilpine alone compared to vehicle reduced mean+/-S.D. subcortical (52+/-24 mm(3) vs. 122+/-64 mm(3), P=0.003) and cortical (35+/-35 mm(3) vs. 125+/-72 mm(3), P=0.00074) infarct volumes. When compared to dizocilpine alone, the combination of RSR13+dizocilpine further reduced subcortical (37+/-14 mm(3) vs. 52+/-24 mm(3), P=0. 034) and cortical (8+/-19 mm(3) vs. 35+/-35 mm(3), P=0.018) infarct size. RSR13+dizocilpine improved neurologic scores vs. either dizocilpine alone (P=0.0014) or vehicle (P=10(-7)). The combination of NMDA receptor antagonism and a RSR13 mediated rightward shift of the oxy-hemoglobin dissociation curve improved outcome from MCAO. Because this occurred after reperfusion, our results suggest that the post-ischemic brain continues to suffer from hypoperfusion defects, which are amenable to therapy by enhanced O(2) delivery. The results also support the concept that neuroprotective strategies, which combine drugs with different mechanisms of action, may yield cumulative benefits.

Aniline Compounds↗
PubMed1999

RSR13, a synthetic allosteric modifier of hemoglobin, improves myocardial recovery following hypothermic cardiopulmonary bypass.

BACKGROUND: During hypothermic blood cardioplegia, oxygen delivery to myocytes is minimal with ineffective anaerobic metabolism predominating. RSR13, 2-[4-[[(3,5-dimethylanilino) carbonyl]methyl]phenoxy]-2-methylpropionic acid, a synthetic allosteric modifier of hemoglobin (Hb), increases release of oxygen from Hb, increasing oxygen availability to hypoxic tissues, and reverses the hypothermia-dependent increase in Hb oxygen affinity. We studied recovery of myocardial mechanical and metabolic function and examined myocardial morphology after cardioplegia, comparing RSR13 (1.75 mmol/L)-supplemented blood (RSR13-BC) to standard blood cardioplegia (BC). METHODS AND RESULTS: Twelve dogs underwent 15 minutes of 37 degrees C global ischemia on cardiopulmonary bypass, followed by 75 minutes of hypothermic cardioplegia (13 degrees C) with either BC (n=6) or RSR13-BC (n=6). There were no differences in baseline function between groups. Cardiac function was assessed after 30 minutes of 37 degrees C reperfusion (BC versus RSR13-BC, respectively) by measuring: % return to normal sinus rhythm (0/100%), % of baseline+dP/dt (33.7+/-1.7/76.3+/-1.9), % of baseline-dP/dt (26.6+/-2.0/81.1+/-1.6), stroke volume (3.5+/-0.5/7.1+/-0.9 mL), cardiac output (340+/-20/880+/-40.3 mL/min), and LVEDP (11.3+/-2.2/0. 3+/-2.9 mm Hg). Postischemic oxidative and metabolic parameters including myocardial lactate, pyruvate, ATP content, and percent water content also were determined. Histological analysis demonstrated preservation of endothelial and myocyte morphology in hearts receiving RSR13-BC compared with BC. CONCLUSIONS: These results indicate that in the setting of hypothermic cardiopulmonary bypass, RSR13 improves recovery of myocardial mechanical and metabolic function compared with standard hypothermic BC. Findings from this study suggest that RSR13-BC, by decreasing hemoglobin oxygen affinity, improves oxidative metabolism and preserves cellular morphology, resulting in significantly improved contractile recovery on reperfusion.

Allosteric Regulation↗
PubMed1999

Effects of RSR13, a synthetic allosteric modifier of hemoglobin, alone and in combination with dizocilpine, on outcome from transient focal cerebral ischemia in the rat.

This study examined the effect of a pharmacologically induced rightward shift in the partial pressure of oxygen at which 50% of hemoglobin is saturated (P50) on outcome from transient focal cerebral ischemia in the rat. Halothane anesthetized rats (n=20 per group) were given saline or a single 15-min infusion of 150 mg/kg RSR13 (2-[4-[[3,5-dimethylanilino) carbonyl]methyl]phenoxy]-2-methylproprionic acid) intravenously before or 30 min after onset of 75 min of middle cerebral artery filament occlusion (MCAO). Seven days later, severity of hemiparesis and cerebral infarct size were examined. RSR13 alone did not significantly improve outcome. Conscious normothermic rats (n=12 per group) were also given RSR13 (150 mg/kg) or 0.9% NaCl intravenously and subjected to 75 min of MCAO with 7 days of recovery. Again, RSR13 alone did not significantly reduce infarct size or improve neurologic score. A dose-response curve for dizocilpine (MK-801) was then constructed in conscious normothermic rats subjected to 75 min of MCAO. Dizocilpine (0.5 mg/kg i.v.) caused a 90% reduction in mean infarct size while 0.25 mg/kg reduced infarct size by 48%. Other rats were then subjected to 75 min of MCAO after being given dizocilpine (0.25 mg/kg i.v.; n=18) or RSR13 (150 mg/kg i.v. )+dizocilpine (0.25 mg/kg i.v.; n=15). RSR13+dizocilpine resulted in smaller cortical infarct volume (8+/-14 mm3 vs. 34+/-37 mm3, p<0.02) and total cerebral infarct volume (46+/-28 mm3 vs. 81+/-60 mm3, p<0. 05) compared to dizocilpine alone, respectively. We conclude that a pre-ischemic peak increase in P50 of approximately 25 mmHg alone is insufficient to reduce focal ischemic injury, but may be advantageous when used in conjunction with other neuroprotective agents.

Allosteric Site↗
PubMed1998

RSR13, a synthetic modifier of hemoglobin-oxygen affinity, enhances the recovery of stunned myocardium in anesthetized dogs.

RSR13 (2-[4-[[(3, 5-dimethylanilino)carbonyl]methyl]phenoxyl]-2-methylpropr ionic acid) is a synthetic allosteric modifier of oxygen (O2)-hemoglobin affinity that increases O2 release to tissue by allosterically stabilizing deoxyhemoglobin. We tested the hypothesis that RSR13 enhances the functional recovery of stunned myocardium in barbiturate-anesthetized dogs instrumented for measurement of left ventricular (LV) and aortic blood pressure, LV +dP/dtmax and subendocardial segment shortening (%SS) in ischemic [left anterior descending (LAD) coronary artery] and normal (left circumflex coronary artery) zones. The partial pressure of oxygen and the Hill coefficient at 50% saturation (P50 and n50, respectively) were determined in arterial blood samples by multiple point tonometry and nonlinear regression analysis. Coronary collateral blood flow in the LAD zone was quantified with radioactive microspheres. Dogs received intravenous vehicle (0.45% saline) or one of two doses of RSR13 (100 or 150 mg.kg-1 bolus followed by a 0.50 or 0.75 mg.kg-1.min-1 infusion, respectively) in a random manner. All dogs were subjected to five 5-min periods of LAD occlusion separated by 5-min periods of reperfusion and followed by 180 min of final reperfusion during which hemodynamics, %SS, arterial blood gases, P50 and n50 were determined at selected intervals. RSR13 caused no hemodynamic effects and coronary collateral blood flow was equivalent among groups. RSR13 increased P50 (+40 +/- 4% for the high dose) and decreased n50 (-31 +/- 2% for the high dose). LAD occlusion caused regional dyskinesia during each 5-min occlusion. Enhanced recovery of %SS by 180 min after final reperfusion was observed in dogs treated with high-dose RSR13 (47 +/- 9% of base line) but not low-dose RSR13 (10 +/- 18% of base line) or vehicle alone (2 +/- 16% of base line). The results suggest that high-dose RSR13 improves the recovery of stunned myocardium throughout reperfusion in open-chest dogs. These findings may be related to increases in O2 availability to ischemic myocardium resulting from RSR13-induced stabilization of the deoxy form of hemoglobin.

Anesthesia↗
PubMed1995

4-(Heteroarylthio)-2-biphenylyltetrazoles as nonpeptide angiotensin II antagonists.

A series of 4-(heteroarylthio)-2-biphenylyltetrazoles was prepared, and the compounds were examined for their ability to displace [3H]AII from angiotensin II receptors. Analogues that exhibited significant receptor binding affinities at less than 10 microM were investigated further for potential antagonism of angiotensin II-mediated contraction of rabbit isolated aortic rings. Three 4-(heteroarylthio)-2-biphenylyltetrazoles were identified that exhibited sub-micromolar angiotensin II receptor binding affinities. These compounds and two reference agents, saralasin and losartan (DUP-753), exhibited concentration-dependent reversal of angiotensin II contraction in isolated aortic rings parallel to their receptor binding affinities. Molecular modeling studies were conducted to examine the conformational effects of the novel sulfide bridging unit contained in these 4-(heteroarylthio)-2-biphenylyltetrazoles. The biological effects of the sulfide bridge as well as alterations in the heteroaromatic moiety were investigated, and the resulting structure--activity relationships are discussed.

Angiotensin II↗
PubMed1995

Lysophosphatidylcholine inhibits relaxation of rabbit abdominal aorta mediated by endothelium-derived nitric oxide and endothelium-derived hyperpolarizing factor independent of protein kinase C activation.

Hypercholesterolemia is associated with increased oxidized LDL and impaired endothelium-dependent relaxation (EDR). An inhibitory component of oxidized LDL is lysophosphatidylcholine (LPC). To determine the effect and mechanism(s) of action of LPC on EDR mediated by endothelium-derived nitric oxide (EDNO) and endothelium-derived hyperpolarizing factor (EDHF), rabbit abdominal aortic rings were suspended for measurement of isometric tension and studied under three conditions: control; with 25 mmol/L K+ buffer to isolate relaxation mediated by EDNO; and in rings treated with N omega-nitro-L-arginine methyl ester (L-NAME, 30 mumol/L) to isolate relaxation mediated by EDHF. Incubation with LPC (10 and 30 mumol/L) for 30 minutes inhibited EDR in a concentration-dependent manner. LPC (30 mumol/L) significantly inhibited maximal relaxation to acetylcholine in control, 25 mmol/L K(+)-, and L-NAME-treated rings (77.1 +/- 7.8%, 42.1 +/- 8.9%, and 3.4 +/- 7.7%) compared with untreated rings (99.0 +/- 0.9%, 90.9 +/- 2.2%, and 54.7 +/- 4.7%, P < .05). Inhibition of relaxation was specific to endothelium-dependent responses in that relaxation to direct smooth muscle vasodilators (papaverine, 8-bromo-cGMP, and sodium nitroprusside) were unaltered by LPC. The inhibition by LPC (30 mumol/L) was not due to cytotoxicity, because EDR returned to normal levels after repeated washing with physiological salt solution containing 0.1% albumin. Co-incubation with protein kinase C inhibitors, staurosporine (20 nmol/L) or calphostin C (1 mumol/L), had no effect on the EDR inhibition by LPC (30 mumol/L). Furthermore, LPC continued to inhibit EDR in rings in which protein kinase C was down-regulated by incubation for 18 hours with 1 mumol/L phorbol 12-myristate 13-acetate (PMA).(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed1993

The pharmacokinetics and pharmacodynamics of the prostacyclin analog 15AU81 in the anesthetized beagle dog.

15AU81, a tricyclic benzindene analog of prostacyclin, is currently under preclinical evaluation as a potential treatment for congestive heart failure. The cardiovascular effects of 15AU81 were evaluated in anesthetized beagle dogs given 4-h infusions at rates of either 0.1, 0.3, 1.0, or 3.0 micrograms/kg/min. Plasma samples taken from these dogs prior to, during, and after the infusion, were analyzed for 15AU81 by a radioimmunoassay (RIA). This report integrates the vasodilatory effects and plasma concentration data from the 15AU81 infusion study. Pharmacokinetic analysis of mean data indicated a biphasic decay of 15AU81 in plasma, with an initial half-life of approximately 2 min, and a terminal half-life of approximately 20 min. Visual inspection of plots of drug effect and drug concentration against time indicated a close relationship between plasma concentration of 15AU81 and the onset of decreases in total peripheral resistance (TPR) and pulmonary vascular resistance (PVR). In general, the decreases in TPR and PVR induced by 15AU81 were maintained during infusion. Concentration-effect plots indicated some hysteresis in TPR vs plasma concentrations of 15AU81 after termination of the infusion; possible explanations for this hysteresis include the presence of saturating concentrations of 15AU81 at the effect site, with a delay in the clearance of 15AU81 from the effect site compared to its clearance from plasma, and/or the presence of active metabolites at the effect site. A fit of the TPR and PVR data to the Emax pharmacodynamic model predicted that the maximum decrease in TPR achievable with 15AU81 in anesthetized dogs was 66%, and that the concentration of 15AU81 producing 50% of the maximum effect (EC50) was 8.6 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Decreased proportion of type I myofibers in skeletal muscle of dogs with chronic heart failure.

BACKGROUND: Whether biochemical and histological abnormalities of skeletal muscle (SM) develop in patients with chronic heart failure (HF) remains controversial. In the present study, dogs with chronic HF were used to examine potential alterations of SM fiber type, fiber size, number of capillaries per fiber (C/F), beta-adrenergic receptor density (Bmax), and fiber ultrastructural integrity. METHODS AND RESULTS: HF was produced in 17 dogs by sequential intracoronary microembolizations. Biopsies of the lateral head of the triceps muscle were used in all studies. Type I and type II fibers were differentiated by myofibrillar ATPase (pH 9.4 or 4.2). Bmax was assessed by radioligand binding and SM ultrastructure by transmission electron microscopy. Comparisons were made with biopsies obtained from nine control dogs. The percentage of SM type I fibers was reduced in HF dogs compared with control dogs (19 +/- 2% versus 32 +/- 5%) (p < 0.001), whereas the percentage of SM type II fibers was increased (81 +/- 2% versus 68 +/- 5%) (p < 0.001). The change in fiber type composition was not associated with a preferential atrophy or hypertrophy of either fiber type. There was no difference in SM Bmax (198.9 +/- 14.3 versus 186.8 +/- 17.3 fmol/mg protein) or in C/F (5.37 +/- 0.26 versus 5.84 +/- 0.21) between HF dogs and control dogs. No ultrastructural abnormalities were present in SM fibers of HF dogs. CONCLUSIONS: In dogs with HF, there is a decrease in the relative composition of the slow-twitch type I SM fibers and an increase in fast-twitch type II fibers. The shift in fiber type composition is not associated with preferential atrophy of either fiber type or with a reduction in C/F, beta-adrenergic receptor density, or structural abnormalities of the myofibers.

Angiography↗
PubMed1992

Myocardial beta adrenoceptor and voltage sensitive calcium channel changes in a canine model of chronic heart failure.

Effects of chronic heart failure upon receptor binding and cardiac function were studied in mongrel dogs. Heart failure was induced by three to seven, graded, sequential, intracoronary microembolizations performed 1 to 3 weeks apart. Depressed systolic and diastolic left ventricular function, reduced cardiac output, increased systemic vascular resistance, increased plasma norepinephrine concentration, left ventricular hypertrophy, and dilation were associated with the development of heart failure in this model. Three months after the last embolization, the density and affinity of myocardial beta adrenoceptors and voltage sensitive calcium channels were quantified by analyzing saturation isotherms of specific radioligand binding. [3H]Dihydroalprenolol and [3H]nitrendipine bound specifically and with high affinity to cardiac beta adrenoceptors and calcium channels, respectively. Scatchard transformation of the specific binding of these radioligands in membranes prepared following intracoronary embolization demonstrated a 47% decrease in the density of [3H]dihydroalprenolol binding sites (605 +/- 20 fmol/mg, normal, vs. 323 +/- 18 fmol/mg, failed; P < 0.05) and a 20% decrease in [3H]nitredipine binding sites (371 +/- 11 fmol/mg, normal, vs. 298 +/- 17 fmol/mg, failed; P < 0.05). The binding equilibrium dissociation constants for [3H]dihydroalprenolol and [3H]nitrendipine were not significantly different between normal and failed myocardium. There was no difference in the sialic acid content in the sarcolemmal membranes prepared from normal and failed dog hearts (31.07 +/- 0.76 nmol/mg, normal, vs. 30.58 +/- 5.25 nmol/mg, failed). This is inconsistent with the selective purification of membranes utilized in these radioligand binding studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Cardiovascular pharmacology of the vasodilator-cardiotonic agent, 349U85.

349U85 is a chemically novel, nonglycoside, noncatecholamine cardiotonic-vasodilator agent with a unique cardiovascular profile in vitro and in vivo. 349U85 and milrinone, 10(-6) to 3 x 10(-5) M each, produce concentration-dependent increases in tension development of 33-60% and 37-60%, respectively, with corresponding 5-18% and 17-55% increases in contractile rate, respectively, in guinea pig spontaneously beating isolated paired atria. In anesthetized dogs, 349U85 at 0.03-1.0 mg/kg i.v. produces dose-dependent increases in left ventricular contractility (dP/dt) of 12-159%, decreases in total peripheral resistance of 11-38%, and increases in heart rate of 3-26%. Milrinone, Cl-914, and enoximone produce comparable increases in dP/dt and decreases in peripheral resistance yet increase the heart rate a maximum of 71, 49, and 41%, respectively. Intra-arterial injection of 349U85 into the vascularly isolated hindlimb of anesthetized dogs produces dose-dependent direct vasodilation. The inotropic effect of 349U85, following a single intravenous dose, is sustained in excess of 4 h while comparable initial inotropic effects of milrinone and enoximone are sustained less than 1 and 2.5 h, respectively. 349U85 effectively reverses acute cardiac depression in anesthetized dogs with a duration exceeding that of milrinone. In conscious dogs, 349U85, at 0.1-1.0 mg/kg p.o., produces a dose-dependent positive inotropic effect (15-73%) with no significant effect on heart rate. Following a single oral dose of 349U85, the inotropic effect is sustained in excess of 6 h. Results of these studies indicate that 349U85 is a potent, long-lasting positive inotropic and vasodilator agent with minimal heart rate effect in vitro and in vivo and is different from a number of reference inodilators.

Animals↗
PubMed1991

The effects of I5AU8I, a chemically stable prostacyclin analog, on the cardiovascular and renin-angiotensin systems of anesthetized dogs [corrected].

15AU81 is a chemically stable tricyclic benzindene analog of prostacyclin. Prostaglandins, PGI2 and PGE2, and their analogs have demonstrated acute hemodynamic benefit in congestive heart failure. The purpose of this study was to evaluate the cardiovascular effects of 15AU81 in anesthetized dogs in order to assess this agent's potential for clinical study in the treatment of congestive heart failure. Four hour intravenous infusions of 15AU81 at 0.1, 0.3, 1.0, or 3.0 micrograms/kg/min produced dose-dependent decreases in mean arterial blood pressure of 10%, 43%, 55% and 68% respectively with associated decreases in total peripheral resistance of 20%, 32%, 56% and 73%, respectively. 15AU81 dilated the pulmonary circulation; however, the effects of 15AU81 on the pulmonary vascular bed were not dose dependent and not stable over time. Maximal decreases in mean pulmonary artery blood pressure achieved were 9%, 23%, 22%, and 18% with an associated decrease in pulmonary vascular resistance of 9%, 33%, 30% and 23%, at doses of 15AU81 of 0.1, 0.3, 1.0 and 3.0 micrograms/kg/min respectively. The onset of vasodilator effects were rapid, reaching a maximum within 5-10 min with an equally rapid recovery when the infusion was discontinued. Cardiac and hormonal effects associated with 15AU81 treatment included decreases in inotropy, and lusitropy and increases in heart rate and plasma angiotensin II concentration. The increase in plasma angiotensin II concentrated correlated significantly with the decrease mean arterial blood pressure. These effects are interpreted to be generally secondary to the potent and profound vasodilator activity of 15AU81 and not likely due to direct cardiac or neurohumoral effects. The hemodynamic profile of 15AU81 suggests that, through its rapid onset and ability to reduce loading conditions of the right and left ventricles and its chemical stability over natural prostacyclin, this prostacyclin analog may have utility in the management of chronic congestive heart failure.

Angiotensin II↗
PubMed1991

Calcium channel blocking and positive inotropic activities of ethyl 5-cyano-1,4-dihydro-6-methyl-2-[(phenylsulfonyl)methyl]-4-aryl-3- pyridine-carboxylate and analogues. Synthesis and structure-activity relationships.

The synthesis and pharmacological evaluation of a series of 2-[(arylsulfonyl)methyl]-4-aryl-5-cyano-1,4-dihydropyridine-3-carboxylic acid esters and analogues are described. These compounds possess a unique profile namely, calcium channel blocking and positive inotropic activities in vitro. Compound 54 was selected as the best compound in the series and was studied in detail. The synthesis and biological profiles of enantiomers of 54 are also reported. The data indicate that although the calcium channel blocking property of 54 is stereospecific the positive inotropic activity is not. Examples of 3- and 6-cyano and other closely related 1,4-dihydropyridine derivatives are described and evaluated for comparison and were found to be devoid of dual activities mentioned above.

Animals↗
PubMed1989

Cardiotonic agents. 9. Synthesis and biological evaluation of a series of (E)-4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl)phenyl]ethenyl]-3 (2H)-pyridazinones: a novel class of compounds with positive inotropic, antithrombotic, and vasodilatory activities for the treatment of congestive heart failure.

A novel series of analogues of (E)-4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl) phenyl]ethenyl]-3(2H)-pyridazinone was synthesized as a variation on the imazodan series. The compounds were evaluated for (i) hemodynamic activity, (ii) cyclic AMP-phosphodiesterase inhibitory activity (human platelets and guinea pig heart tissue), and (iii) platelet aggregation inhibitory activity. The insertion of the ethenyl moiety between the phenyl and dihydropyridazinone rings produced novel compounds that retained the potent inotropic/vasodilator activity of the parent imazodan series and enhanced the platelet aggregation inhibitory potency. Compound 3d, the most potent in this series, demonstrated in vivo antithrombotic activity. The synthesis and the biological activity of these new pyridazinone analogues are reported.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

Species differences in the positive inotropic response to DPI 201-106, a novel cardiotonic agent.

The positive inotropic activity of the novel cardiotonic DPI 201-106 was investigated in rat and guinea pig isolated hearts. For comparative purposes, the adenylate cyclase stimulant forskolin and the sodium channel agonist veratridine were also evaluated in both species. DPI 201-106 and veratridine produced greater inotropic effects in rat hearts than in guinea pig hearts, whereas forskolin produced comparable effects. In both species the inotropic response to DPI 201-106 and veratridine, but not forskolin, was reversed by the sodium channel antagonist tetrodotoxin. These results confirm that the positive inotropic effect of DPI 201-106 is due to stimulation of the sodium channel and demonstrate for the first time that species differences exist in the inotropic response to this novel cardiotonic drug.

Animals↗
PubMed1989

PD 122860: a novel dihydropyridine with sodium channel stimulating and calcium channel blocking properties.

The cardiac and vascular activities of ethyl 5-cyano-1,4-dihydro-6-methyl-2-[(4-pyridinyl-sulfonyl)methyl]-4-[2- (trifluoromethyl)phenyl]-3-pyridine carboxylase (PD 122860), a novel dihydropyridine, were investigated in vitro using rat heart and rabbit aorta, and compared with reference inotropic and vasodilator agents. In the rat heart, PD 122860 increased left ventricular contractility, decreased coronary resistance and altered the shape of the electrocardiogram T-wave. All three effects were observed at comparable concentrations of PD 122860. The inotropic response to PD 122860 was reversed by the Na+ channel blocker tetrodotoxin and blunted by the Na+-Ca++ exchange inhibitor dichlorobenzamil. The effects of tetrodotoxin and dichlorobenzamil on the inotropic response to the reference Na+ channel stimulant veratridine were comparable to PD 122860, whereas tetrodotoxin and dichlorobenzamil had no inhibitory effect on the inotropic responses to the adenylate cyclase stimulator forskolin or the Ca++ channel stimulant BAY K 8644. PD 122860 selectively relaxed potassium-contracted aortic rings and inhibited [3H]nitrendipine binding to rat brain membranes, suggesting that the vasodilator activity of PD 122860 is due to Ca++ channel blockade. In contrast to BAY K 8644, PD 122860 did not contract partially depolarized aortic rings, suggesting an absence of Ca++ channel stimulant activity. PD 122860 is a racemic mixture and both the vasorelaxant and [3H]nitrendipine binding inhibitory activities selectively reside in the (+)-enantiomer [(+)-PD 122860]. In contrast, the inotropic response resides with both enantiomers of PD 122860. It is therefore concluded that PD 122860 represents a unique dihydropyridine derivative which possesses both Na+ channel stimulating and Ca++ channel blocking activities.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗