Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-09-10
2000-12-26
Jordan, Kimberly
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514375, 514866, A61K 3144, A61K 3142
Patent
active
061660493
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a novel method of treatment, in particular for the treatment of Syndrome X and certain compounds used in said method.
It is known that the .gamma.-isoform of peroxisome proliferator-activated receptor (herein after PPAR.gamma.) is member of a nuclear receptor superfamily that includes receptors for the steroid, thyroid and retinoid hormones(Evans, Science 240, 889-895, (1988)). It is also known from Chawla et al that PPAR.gamma. is expressed early during the differentiation of adipocytes (Endocrinology 135,798-800, 1994).
Spiegelman et al state in Cell (Vol 83, 803-812, 1995) that signals which modulate PPAR.gamma. activity may serve a primary role in regulating energy homeostasis. They conclude (ibid, 810) that `screening for potent PPAR.gamma. agonists and antagonists represents a logical and potentially rapid approach towards the development of novel therapeutic agents for NIDDM and obesity respectively.`.
It is known that the .alpha.-isoform of peroxisome proliferator-activated receptor (herein after PPAR.alpha.) acts to stimulate peroxisomal proliferation in the rodent liver which leads to enhanced fatty oxidation by this organ (Keller and Wahli: Trends Endocrin Metab 1993;4:291-296). Hypolipidaemic agents have the ability to stimulate PPAR alpha and the ensuing stimulation of peroxisomal proliferation and consequent fatty acid oxidation can account for the reduction in plasma fatty acids (Macdonald and Lane: Current Biology Vol5 pp618-621 (1995)).
Syndrome X is the syndrome characterised by an initial insulin resistant state, generating hyperinsulinaemia, dyslipidaemia and impaired glucose tolerance, which can progress to non-insulin dependent diabetes mellitus (Type II diabetes), characterised by hyperglycaemia and which then further progresses to diabetic complications.
We now consider that inclusion of PPAR.alpha. effects in a PPAR.gamma. antihyperglycaemic agent will result in a reagent with enhanced therapeutic potential in the syndrome X aetiology due to an enhanced hypolipidaemic effect.
International Patent Application number PCT/EP 95/03038 discloses certain compounds of formula (A): ##STR1## or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein R.sup.a represents 2-benzoxazolyl or 2-pyridyl and R.sup.b represents CH.sub.2 OCH.sub.3 or CF.sub.3.
The compounds of formula (A) are stated to be of potential use in the treatment and/or prophylaxis of hyperglycaemia, especially in Type II diabetes, hyperlipidaemia, hypertension, cardiovascular disease, especially atherosclerosis and of renal disease, especially renal disease associated with the development of Type II diabetes including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease and for the prevention, reversal, stabilisation or retardation of the progression of microalbuminuria to albuminuria.
It has now been discovered that the compounds of formula (A) exhibit agonist activity at both PPAR.alpha. and PPAR.gamma. and that as well as being particularly effective for the treatment and/or prophylaxis of hyperglycaemia they are also now considered to be most effective for the treatment and/or prophylaxis of pre-diabetic insulin resistance syndrome and the resulting complications thereof: They are therefore considered to be useful for the treatment and/or prophylaxis of insulin resistance, diabetes, dyslipidaemia, atherosclerosis, hypertension, cardiovascular disease and obesity.
Accordingly, in a first aspect the invention provides a method for the treatment and/or prophylaxis of Syndrome X in a human or non-human mammal, which method comprises the administration of an effective, non-toxic and pharmaceutically effective amount of an agonist of PPAR.alpha. and PPAR.gamma., or a pharmaceutically acceptable derivative thereof, to a human or non-human mammal in need of such treatment.
Thus, one aspect of the invention is the treatment of Syndrome X.
A further aspect of the invent
REFERENCES:
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Lehmann et al., "An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor .gamma. (PPAR.gamma.)", The Journal of Biological Chemistry, vol. 270, No. 22, pp. 12953-12956 (1995).
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Baumeister Kirk
Jordan Kimberly
King William T.
SmithKline Beecham p.l.c.
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