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Am J Physiol Heart Circ Physiol 286: H1177-H1184, 2004. First published November 13, 2003; doi:10.1152/ajpheart.00652.2003
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Cardioprotective effects of ingliforib, a novel glycogen phosphorylase inhibitor

W. Ross Tracey,1 Judith L. Treadway,1 William P. Magee,1 Jill C. Sutt,1 R. Kirk McPherson,1 Carolyn B. Levy,1 Donald E. Wilder,1 Li J. Yu,2 Yue Chen,2 Ravi M. Shanker,3 Alison K. Mutchler,3 Andrew H. Smith,1 David M. Flynn,1 and Delvin R. Knight1

1Department of Cardiovascular and Metabolic Diseases, 2Department of Pharmacokinetics, Dynamics and Metabolism, and 3Pharmaceutical Research and Development, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut 06340

Submitted 10 July 2003 ; accepted in final form 6 November 2003

Interventions such as glycogen depletion, which limit myocardial anaerobic glycolysis and the associated proton production, can reduce myocardial ischemic injury; thus it follows that inhibition of glycogenolysis should also be cardioprotective. Therefore, we examined whether the novel glycogen phosphorylase inhibitor 5-Chloro-N-{(1S,2R)-3-[(3R,4S)-3,4-dihydroxy-1-pyrrolidinyl)]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl}-1H-indole-2-carboxamide (ingliforib; CP-368,296) could reduce infarct size in both in vitro and in vivo rabbit models of ischemia-reperfusion injury (30 min of regional ischemia, followed by 120 min of reperfusion). In Langendorff-perfused hearts, constant perfusion of ingliforib started 30 min before regional ischemia and elicited a concentration-dependent reduction in infarct size; infarct size was reduced by 69% with 10 µM ingliforib. No significant drug-induced changes were observed in either cardiac function (heart rate, left ventricular developed pressure) or coronary flow. In open-chest anesthetized rabbits, a dose of ingliforib (15 mg/kg loading dose; 23 mg·kg–1·h–1 infusion) selected to achieve a free plasma concentration equivalent to an estimated EC50 in the isolated hearts (1.2 µM, 0.55 µg/ml) significantly reduced infarct size by 52%, and reduced plasma glucose and lactate concentrations. Furthermore, myocardial glycogen phosphorylase a and total glycogen phosphorylase activity were reduced by 65% and 40%, respectively, and glycogen stores were preserved in ingliforib-treated hearts. No significant change was observed in mean arterial pressure or rate-pressure product in the ingliforib group, although heart rate was modestly decreased postischemia. In conclusion, glycogen phosphorylase inhibition with ingliforib markedly reduces myocardial ischemic injury in vitro and in vivo; this may represent a viable approach for both achieving clinical cardioprotection and treating diabetic patients at increased risk of cardiovascular disease.

ischemia; reperfusion; heart; infarct; rabbit


Address for reprint requests and other correspondence: W. Ross Tracey, Pfizer Global Research and Development, MS8220-3125, Eastern Point Rd., Groton, CT 06340 (E-mail: w_ross_tracey{at}groton.pfizer.com).




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