In this paper we show that 4-aryl-CH2-imidazole-substituted benzopyran compounds with 3S,4R-stereochemistry are cardioprotective by inhibiting the F1F0 mitochondrial ATP hydrolase. Compounds (e.g., 13) with 3R,4S-stereochemistry act as mitochondrial KATP openers. This resulted from an inversion of stereochemistry for the F1F0 mitochondrial ATP hydrolase vs mitochondrial KATP. Structure-activity relationships for the inhibition of mitochondrial ATP hydrolase are also delineated. It is not clear how 13 (3R,4S) can selectively inhibit the hydrolytic activity of the F1F0 mitochondrial enzyme without interfering with the synthase activity.

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Compounds (IX) exhibit excellent potency and selectivity. -(HAMANN*, L. G.; DING, C. Z.; MILLER, A. V.; MADSEN, C. S.; WANG, P.; STEIN, P. D.; PUDZIANOWSKI, A. T.; GREEN, D. W.; MONSHIZADEGAN, H.; ATWAL, K. S.; Bioorg. Med. Chem. Lett. 14 (2004) 4, 1031-1034; Dep. Discovery Chem., Bristol-Myers Squibb Pharm. Res. Inst., Princeton, NJ 08543, USA; Eng.) -M. Paetzel 23-178