Abstract
A series of isoflavone and tyrphostin compounds were found to inhibit the degradation of cAMP by several cyclic nucleotide phosphodiesterase (PDE) isozymes. Specific hydroxyl groups on the isoflavone structure were critical for PDE isozyme-selective inhibition. Replacement of the C-7 hydroxyl group of the isoflavone with a methoxy group raised the IC50 for PDE1, PDE3, and PDE4. The absence of the C-5 hydroxyl group raised the IC50from 5 to >100 μM for PDE4, but actually lowered the IC50 for PDE3 and PDE1. Replacement of the C-4′ hydroxyl group with a methoxy group raised the IC50 for PDE3 and PDE1, yet only slightly changed the IC50 for PDE4. Various tyrphostins were also potent inhibitors of PDE1, PDE3, and PDE4. The four-carbon side chained tyrphostins were much less potent; however, a very interesting pattern was observed in which removal of phenolic hydroxyls on the tyrphostin structure increased the potency for PDE1 and PDE3, but not PDE4. These results may help to explain some of the therapeutic and intracellular signaling effects of isoflavones and tyrphostins. Moreover, the isozyme selectivity demonstrated by the isoflavones and tyrphostins can serve as a pharmacophore for the design of specific PDE inhibitors.
Footnotes
- Received August 10, 1999.
- Accepted December 20, 1999.
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Send reprint requests to: Dr. Bruce H. Morimoto, Phoenix International Life Sciences, Inc., 2025 Helena Way, Redwood City, CA 94061. E-mail: morimoto{at}mciworld.com
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This work was supported, in part, by the National Institutes of Health, NS33230; by a predoctoral fellowship to M.R.N. from the American Heart Association, Indiana Affiliate; and by funding to B.H.M. as a Cottrell Scholar of the Research Corporation.
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1 Present address: Dept. of Pharmacology, Mayo Clinic Jacksonville, 4500 San Pablo Rd., Jacksonville, FL 32224. E-mail:nichols.michael{at}mayo.edu
- The American Society for Pharmacology and Experimental Therapeutics
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