Method of identification of inhibitors of PDE1C

Details Method of identification of inhibitors of PDE1C Method of identification of inhibitors of PDE1C

1999-02-05

2002-07-09

Tate, Christopher R. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C435S006120, C435S007710, C435S014000, C435S196000, C435S199000, C435S252300, C435S325000, C435S354000, C435S372200, C435S377000, C514S866000

Reexamination Certificate

active

06417208

ABSTRACT:

BACKGROUND OF THE INVENTION
Diabetes is a group of diseases characterized by, among other features, defects in the regulation of glucose utilization and metabolism, resulting in impaired glucose tolerance. Despite the availability of insulin replacement therapy and a number of other therapeutic medications, which have reduced the acute mortality associated with diabetic ketoacidosis, insulin-treated patients inevitably develop long-term complications that may result in renal failure, loss of sight, as well as chronic and debilitating peripheral and cardiovascular disease. The major forms of diabetes include insulin-dependent diabetes mellitus, characterized by a deficiency of endogenous insulin secretion and non-insulin-dependent diabetes mellitus, characterized by a relative resistance of body tissues to circulating insulin. Both types of diabetes respond to administration of exogenous insulin. The various commercially available insulin preparations are protein materials that must be injected and that are associated with all of the other disadvantages that accompany the administration of foreign proteins to a patient. Previous efforts to provide oral therapeutic agents have resulted in oral hypoglycemic agents, such as the sulfonylureas, that are believed to act primarily by stimulating endogenous insulin secretion. Nevertheless, both the first and second generation sulfonylureas suffer from a number of drawbacks including hypoglycemia especially when associated with renal impairment and have been associated with a number of health risks, such as hypoglycemia and adverse effects in the cardiovascular and the central nervous system. In addition, cell replacement therapy harbors severe risks of transfer of infectious agents.
It is known that pancreatic &bgr;-cells contain several cyclic nucleotide phosphodiesterases that can be activated under different physiological conditions to lower the levels of cyclic AMP and reduce insulin secretion. Thus, it has been thought that inhibition of cyclic nucleotide phosphodiesterases of pancreatic &bgr;-cells would be a potentially powerful approach to enhancing insulin secretion in a glucose dependent fashion which also circumvents the development of the adverse effects of hypoglycemia. Pancreatic &bgr;-cells contain several cyclic nucleotide phosphodiesterases that can be activated under different physiological conditions to lower the levels of cyclic AMP and reduce insulin secretion.
For this reason, attempts have been made to identify those nucleotide phosphodiesterases that function in concert with glucose to limit insulin secretion, and which lack a strong requirement for additional hormonal or neural stimulation. Identification of such cyclic nucleotide phosphodiesterases would also provide valuable targets for the development of novel anti-hyperglycemic agents. However, to date, previous efforts to identify pancreatic &bgr;-cell phosphodiesterases relevant to glucose dependent insulin secretion have been unsuccessful. Contradictory results have been reported by several studies that implicate PDE3 in regulation of glucose dependent insulin secretion (Shafiee-Nick et al.,
Br J Pharmacol
. 115:1486-92, 1995; Parker et al.,
Biochem Biophys Res Commun
. 217:916-23, 1995; Leibowitz et al.,
Diabetes
44:67-74, 1995; Zhao et al.,
Proc Natl Acad Sci U S A
94: 3223-8, 1997). Data concerning PDE4 is controversial (Shafiee-Nick et al.,
Br J Pharmacol
. 115:1486-92, 1995; Parker et al.,
Biochem Biophys Res Commun
. 217:916-23, 1995; Leibowitz et al.,
Diabetes
44:67-74, 1995; Zhao et al., Proc Natl Acad Sci U S A 94: 3223-8, 1997). However, more current studies demonstrate effects of PDE3 only in the presence of hormone regulators like insulin like growth factor 1 and leptin (Zhao et al.,
Proc Natl Acad Sci U S A
94:3223-8, 1997; Zhao et al.,
J.Clin.Invest
. 102:869-872, 1998). Further, these studies show that PDE4 does not affect insulin secretion under these circumstances (Zhao et al., Proc Natl Acad Sci U S A 94:3223-8, 1997; Zhao et al.,
J.Clin.Invest.
102:869-872, 1998). In addition, the presence of PDE3 in adipocytes and in liver and its contribution to insulin action in these tissues, make that enzyme an unsuitable target for the treatment of hyperglycemia. Accordingly, in vivo administration of PDE3 inhibitors to rats failed to affect fasting or post-glucose plasma glucose levels (El-Metwally et al.,
Eur J Pharmacol
. 324:227-32, 1997, Parker et al.
Biochem Biophys Res Commun
. 236:665-9, 1997).
Complications associated with insulin administration involve the introduction of foreign proteins to patients, and with cell replacement therapy the introduction of infectious agents. Complications associated with oral hypoglycemia agents involve the uncoupling of insulin secretion from nutritional, hormonal and neural regulation, hypoglycemia and other adverse effects. For these reasons, there remains a need in the art for new agents useful in the treatment of the various types of diabetes and for new methods of identifying such agents.
Pancreatic &bgr;-cells contain multiple cyclic nucleotide phosphodiesterases that lower cAMP levels and reduce insulin secretion. Inhibition of &bgr;-cell cAMP phosphodiesterases can augment insulin secretion in a nutrient, hormone and neural sensitive fashion, and thus provide a powerful approach for regulating or increasing insulin secretion. Thus far, &bgr;-cell cyclic nucleotide phosphodiesterases that can serve as targets for regulating or increasing insulin secretion were not identified (Shafiee-Nick et al.,
Br. J. Pharmacol
. 115:1486-92, 1995; Parker et al.,
Biochem. Biophys. Res. Commun
. 217:916-23, 1995; Leibowitz et al.,
Diabetes
44:67-74, 1995; Zhao et al.,
Proc. Natl. Acad. Sci. USA
94: 3223-8, 1997; Zhao et al.,
J. Clin. Invest
. 102:869-872, 1998; El-Metwally et al.,
Eur. J. Pharmacol
. 324:227-32, 1997, Parker et al.,
Biochem. Biophys. Res. Commun
. 236:665-9, 1997.
The second messengers cAMP and cGMP mediate diverse physiological responses to hormones, neurotransmitters and light. Rates of cyclic nucleotide synthesis by cyclases and of their degradation by phosphodiesterases (PDEs) regulate their cellular concentrations (reviewed in Beavo, J. A. (1995)
Physiol. Rev
. 75, 725-748 and Houslay, M. D. and Milligan, G. (1997)
TIBS
217-224). Cyclic nucleotide PDEs have been distinguished into nine families based on their substrate affinity and specificity, their selective sensitivity to cofactors and inhibitory drugs. Cyclic nucleotide PDE families are: (1) PDE1—Ca
+2
/calmodulin stimulated PDEs; (2) PDE2—cGMP stimulated PDEs; (3) PDE3—cGMP inhibited PDEs; (4) PDE4—cAMP specific PDEs; (5) PDE5—cGMP specific PDEs; (6) PDE6—photoreceptor PDEs; and (7) PDE7—higher affinity cAMP specific PDEs; (8) PDE8—cAMP specific IBMX resistant PDEs (Fisher, et al.(1998)
Biochem. Biophys. Res. Commun
. 246, 570-577; Hayashi, et al. (1998)
Biochem. Biophys. Res. Commun
. 250, 751-756; Soderling, et al. (1998)
Proc. Natl. Acad. Sci. USA
95, 8991-8996); (9) PDE9—cGMP specific IBMX resistant PDEs (Fisher, et al. (1998)
J. Biol. Chem
. 273, 15559-15564 and Soderling, et al. (1998)
J. Biol. Chem
. 273, 15553-15558). All mammalian PDEs contain a related C-terminal domain with ~30% sequence identity between families, and N-terminal regulatory domains containing cofactor or cGMP binding sites, localization and other regulatory sequences. Both tissue and cell specific gene expression, and a variable splicing pattern, contribute to the unique and complex composition of cyclic nucleotide PDEs in mammalian cells normally containing activities derived from several families of PDEs (Beavo, J. A. (1995)
Physiol. Rev
. 75, 725-748 and Houslay, M. D. and Milligan, G. (1997)
TIBS
217-224). PDE inhibitors that do not affect adenosine uptake and exhibit high selectivity between PDE families, and in some cases between PDE isozymes, are powerful tools for identification of PDEs involved in diverse physiological responses (Ballard, et al. (1998)
J Urol
159, 2164-2171; Giembycz, et al. (1996)
J. Pha

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