Joseph J. Lynch

Therapeutic potential of modulating potassium currents in the diseased myocardium.

Myocardial disease states are characterized by multiple electrophysiologic abnormalities, including alterations in potassium channel activities. During acute myocardial ischemia, activation of ATP‐regulated K+ current (IK(atp)) results in shortening of action potential duration and elevation of extracellular K+ concentration. In hypertrophied myocardium, increases in inward rectifier K+ current (IK1) and decreases in delayed rectifier K+ current (IK) are observed. Alterations in K+ channel activity in myocardial disease states suggest the potential to therapeutically modify cardiac rhythm and function with K+ channel modulators. Glass III antiarrhythmic agents, which prolong myocardial refractoriness predominantly via a blockade of IK, have demonstrated efficacy in suppressing reentrant atrial and ventricular arrhythmias in animal models as well as promising efficacy in initial clinical studies. Potassium channel openers (PCOs), which activate cardiac IK(ATP), have demonstrated both antiarrhythmic and proarrhythmic activities in various experimental settings, and also are being investigated as potential cardioprotective agents. Sulfonylureas, which block cardiac Ik(ATP), also have been investigated as potential antiarrhythmic agents with equivocal results, and have displayed a propensity to exacerbate ischemic myocardial dysfunction in experimental studies. A more comprehensive understanding of K+ channel activity in various myocardial disease states, including concomitant disorders such as myocardial ischemia and hypertrophy, will facilitate the development of more useful potassium channel modulators, as well as a clearer recognition of the undesirable effects of such agents.— Lynch, J. J.; Sanguinetti, M. C.; Kimura, S.; Bassett, A. L. Therapeutic potential of modulating potassium currents in the diseased myocardium. FASEB J. 6: 2952‐2960; 1992.

Synthesis of functionalized furo[2,3-b]pyridines via the Pd-catalyzed coupling of acetylenes to iodopyridones. Preparation of a key intermediate to a new HIV protease inhibitor L-754,394

Abstract The synthesis of 1 was accomplished in 55% overall yield via the Pd-catalyzed coupling of 3 and 4 followed by Cu-catalyzed cyclization of the resulting intermediate 2.

MK-0448, a specific Kv1.5 inhibitor: safety, pharmacokinetics, and pharmacodynamic electrophysiology in experimental animal models and humans.

Background— We evaluated the viability of IKur as a target for maintenance of sinus rhythm in patients with a history of atrial fibrillation through the testing of MK-0448, a novel IKur inhibitor. Methods and Results— In vitro MK-0448 studies demonstrated strong inhibition of IKur with minimal off-target activity. In vivo MK-0448 studies in normal anesthetized dogs demonstrated significant prolongation of the atrial refractory period compared with vehicle controls without affecting the ventricular refractory period. In studies of a conscious dog heart failure model, sustained atrial fibrillation was terminated with bolus intravenous MK-0448 doses of 0.03 and 0.1 mg/kg. These data led to a 2-part first-in-human study: Part I evaluated safety and pharmacokinetics, and part II was an invasive electrophysiological study in healthy subjects. MK-0448 was well-tolerated with mild adverse experiences, most commonly irritation at the injection site. During the electrophysiological study, ascending doses of MK-0448 were administered, but no increases in atrial or ventricular refractoriness were detected, despite achieving plasma concentrations in excess of 2 &mgr;mol/L. Follow-up studies in normal anesthetized dogs designed to assess the influence of autonomic tone demonstrated that prolongation of atrial refractoriness with MK-0448 was markedly attenuated in the presence of vagal nerve simulation, suggesting that the effects of IKur blockade on atrial repolarization may be negated by enhanced parasympathetic neural tone. Conclusions— The contribution of IKur to human atrial electrophysiology is less prominent than in preclinical models and therefore is likely to be of limited therapeutic value for the prevention of atrial fibrillation.Background— We evaluated the viability of IKur as a target for maintenance of sinus rhythm in patients with a history of atrial fibrillation through the testing of MK-0448, a novel IKur inhibitor.nnMethods and Results— In vitro MK-0448 studies demonstrated strong inhibition of IKur with minimal off-target activity. In vivo MK-0448 studies in normal anesthetized dogs demonstrated significant prolongation of the atrial refractory period compared with vehicle controls without affecting the ventricular refractory period. In studies of a conscious dog heart failure model, sustained atrial fibrillation was terminated with bolus intravenous MK-0448 doses of 0.03 and 0.1 mg/kg. These data led to a 2-part first-in-human study: Part I evaluated safety and pharmacokinetics, and part II was an invasive electrophysiological study in healthy subjects. MK-0448 was well-tolerated with mild adverse experiences, most commonly irritation at the injection site. During the electrophysiological study, ascending doses of MK-0448 were administered, but no increases in atrial or ventricular refractoriness were detected, despite achieving plasma concentrations in excess of 2 μmol/L. Follow-up studies in normal anesthetized dogs designed to assess the influence of autonomic tone demonstrated that prolongation of atrial refractoriness with MK-0448 was markedly attenuated in the presence of vagal nerve simulation, suggesting that the effects of IKur blockade on atrial repolarization may be negated by enhanced parasympathetic neural tone.nnConclusions— The contribution of IKur to human atrial electrophysiology is less prominent than in preclinical models and therefore is likely to be of limited therapeutic value for the prevention of atrial fibrillation.

Rate-Dependent Effects of Vernakalant in the Isolated Non-Remodeled Canine Left Atria Are Primarily Due to Block of the Sodium Channel Comparison with Ranolazine and dl-Sotalol

Background— Several clinical trials have shown that vernakalant is effective in terminating recent onset atrial fibrillation (AF). The electrophysiological actions of vernakalant are not fully understood. Methods and Results— Here we report the results of a blinded study comparing the in vitro canine atrial electrophysiological effects of vernakalant, ranolazine, and dl-sotalol. Action potential durations (APD50,75,90), effective refractory period (ERP), post repolarization refractoriness (PRR), maximum rate of rise of the action potential (AP) upstroke (Vmax), diastolic threshold of excitation (DTE), conduction time (CT), and the shortest S1-S1 permitting 1:1 activation (S1-S1) were measured using standard stimulation and microelectrode recording techniques in isolated normal, non-remodeled canine arterially perfused left atrial preparations. Vernakalant caused variable but slight prolongation of APD90 (P=not significant), but significant prolongation of APD50 at 30 &mgr;mol/L and rapid rates. In contrast, ranolazine and dl-sotalol produced consistent concentration- and reverse rate-dependent prolongation of APD90. Vernakalant and ranolazine caused rate-dependent, whereas dl-sotalol caused reverse rate-dependent, prolongation of ERP. Significant rate-dependent PRR developed with vernakalant and ranolazine, but not with dl-sotalol. Other sodium channel-mediated parameters (ie, Vmax, CT, DTE, and S1-S1) also were depressed significantly by vernakalant and ranolazine, but not by dl-sotalol. Only vernakalant elevated AP plateau voltage, consistent with blockade of ultrarapid delayed rectified potassium current and transient outward potassium current. Conclusions— In isolated canine left atria, the effects of vernakalant and ranolazine were characterized by use-dependent inhibition of sodium channel-mediated parameters, and those of dl-sotalol by reverse rate-dependent prolongation of APD90 and ERP. This suggests that during the rapid activation rates of AF, the INa blocking action of the mixed ion channel blocker vernakalant takes prominence. This mechanism may explain vernakalants anti-AF efficacy.

A NOVEL SYNTHESIS OF DISUBSTITUTED UREAS USING TITANIUM(IV) ISOPROPOXIDE AND SODIUM BOROHYDRIDE

This paper describes a high yield preparation of unsymmetrically disubstituted ureas by a titanium(IV) isopropoxide/sodium borohydride mediated reductive amidation of aromatic aldehydes with monosubstituted ureas.

Asymmetric synthesis of cis-2,5-disubstituted pyrrolidine, the core scaffold of β3-AR agonists.

A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular N→C benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of β3-AR agonists is synthesized in 38% overall yield.

Practical and cost-effective manufacturing route for the synthesis of a β-lactamase inhibitor.

Compound 1, a potent and irreversible inhibitor of β-lactamases, is in clinical trials with β-lactam antibiotics for the treatment of serious and antibiotic-resistant bacterial infections. A short, scalable, and cost-effective route for the production of this densely functionalized polycyclic molecule is described.

Comparison of electrophysiological and antiarrhythmic effects of vernakalant, ranolazine, and sotalol in canine pulmonary vein sleeve preparations

BACKGROUNDnVernakalant (VER) is a relatively atrial-selective antiarrhythmic drug capable of blocking potassium and sodium currents in a frequency- and voltage-dependent manner. Ranolazine (RAN) is a sodium-channel blocker shown to exert antiarrhythmic effects in pulmonary vein (PV) sleeves. dl-Sotalol (SOT) is a β-blocker commonly used in the rhythm-control treatment of atrial fibrillation. This study evaluated the electrophysiological and antiarrhythmic effects of VER, RAN, and SOT in canine PV sleeve preparations in a blinded fashion.nnnMETHODSnTransmembrane action potentials were recorded from canine superfused PV sleeve preparations exposed to VER (n = 6), RAN (n = 6), and SOT (n = 6). Delayed afterdepolarizations were induced in the presence of isoproterenol and high-calcium concentrations by periods of rapid pacing.nnnRESULTSnIn PV sleeves, VER, RAN, and SOT (3-30 μM) produced small (10-15 ms) increases in action potential duration. The effective refractory period, diastolic threshold of excitation, and the shortest S(1)-S(1) cycle length permitting 1:1 activation were significantly increased by VER and RAN in a rate- and concentration-dependent manner. VER and RAN significantly reduced V(max) in a concentration- and rate-dependent manner. SOT did not significantly affect the effective refractory period, V(max), diastolic threshold of excitation, or the shortest S(1)-S(1) cycle length permitting 1:1 activation. All 3 agents (3-30 μM) suppressed delayed afterdepolarization-mediated triggered activity induced by isoproterenol and high calcium.nnnCONCLUSIONSnIn canine PV sleeves, the effects of VER and RAN were similar and largely characterized by concentration- and rate-dependent depression of sodium-channel-mediated parameters, which were largely unaffected by SOT. All 3 agents demonstrated an ability to effectively suppress delayed afterdepolarization-induced triggers of atrial arrhythmia.

Negative lusitropic effect of DPI 201-106 and E4031. Possible role of prolonging action potential duration

In open-chest anesthetized dogs, the time constant of isovolumic left ventricular pressure decay increased following the intravenous administration of either E4031, a class III antiarrhythmic agent which acts by K+ channel blockade, or DPI 201-106 (DPI), a cardiotonic agent which acts by delaying Na+ channel inactivation. In addition to prolonging cardiac refractoriness, both E4031 and DPI increased left ventricular +dP/dt but without significantly altering -dP/dt. Consequently, the value of the ratio (+dP/dt)/(-dP/dt) increased. There were no significant changes in heart rate, mean arterial pressure, or left ventricular end diastolic pressure. Since both E4031 and DPI prolonged the action potential duration (APD) and the refractory period, and slowed relaxation in vivo, the possibility of a causal link between these effects was further investigated under in vitro conditions. In isometrically contracting rabbit papillary muscles, E4031 and DPI increased peak developed tension (DT) and its maximal rate of rise (+T). Since the maximal rate of fall of DT (-T) did not increase by the same factor that +T increased, the value of the ratio +T/-T increased. Time to half relaxation increased, whereas time to peak tension was not significantly changed by either E4031 or DPI. These negative lusitropic effects produced by E4031 or DPI were not observed when equivalent increases in contractility were produced by increasing the extracellular Ca2+ concentration. The effective refractory period measured in the papillary muscles increased following superfusion with either of the two drugs, consistent with their known ability to increase APD. A causal link between the prolongation of APD and the negative lusitropic effects of E4031 and DPI is postulated as the possible mechanism.

Synthesis of a new generation reverse transcriptase inhibitor via the BCl3/GaCl3-induced condensation of anilines with nitriles (sugasawa reaction)

Abstract The synthesis of 1 was achieved in high overall yield through a mechanism-based improvement of the preparation of o-acyl anilines.