SR 202

IC50: 140 μM for attenuation of troglitazone-induced peroxisome proliferator-activated receptor gamma (PPAR) transcriptional activity [1]

The phosphonophosphate SR-202 [(S)-(4-chlorophenyl)(dimethoxyphosphoryl)methyl dimethyl phosphate] is a PPAR antagonist, which inhibits both TZD-stimulated recruitment of the coactivator steroid receptor coactivator-1 and TZD-induced transcriptional activity of the receptor. PPAR is a nuclear receptor which regulates glucose metabolism and fatty acid storage.

In vitro: SR-202 is a specific antagonist of PPAR, which shows selectivity both among the PPAR family members and other nuclear receptors. SR-202 also Inhibits PPAR-dependent differentiation of adipocytes. In cell culture, SR-202 efficiently antagonizes hormone- and TZD induced adipocyte differentiation [1].

In vivo:. Decreasing PPAR activity by treatment with SR-202 leads to a reduction of both high fat diet-induced adipocyte hypertrophy and insulin resistance. Treatment with SR-202 also dramatically improves insulin sensitivity in the diabetic ob/ob mice [1]. When wild-type mice are fed a high-fat diet, the plasma levels of TNF-α are raised, and SR-202 treatment protects against this rise [2]..

Clinical trial: So far, no clinical study has been conducted.

References:
[1] Rieusset J, Touri F, Michalik L, Escher P, Desvergne B, Niesor E, Wahli W.  A new selective peroxisome proliferator-activated receptor gamma antagonist with antiobesity and antidiabetic activity. Mol Endocrinol. 2002 Nov;16(11):2628-44.
[2] Doggrell S.  Do peroxisome proliferation receptor-gamma antagonists have clinical potential as combined antiobesity and antidiabetic drugs Expert Opin Investig Drugs. 2003 Apr;12(4):713-6.

Clinical experience with the Fraxel SR laser: 202 treatments in 59 consecutive patients.[Pubmed:18453942]

Plast Reconstr Surg. 2008 May;121(5):297e-304e.

BACKGROUND: The authors investigated postprocedure patient satisfaction after fractional photothermolysis with the Fraxel SR laser. METHODS: All patients were surveyed with respect to their satisfaction with the results using a Likert scale ranging from 1 to 5, with 5 = extremely satisfied and 1 = extremely dissatisfied. Fraxel SR laser treatment was performed for categories of skin abnormalities that included dyschromia, scarring, and texture abnormalities. Most patients had more than one concern. Univariate and multivariate analyses were performed. Logistic regression was used to explore predictors of a satisfaction score of 4 or 5. RESULTS: Fifty-nine patients (median age, 52 years; range, 30 to 71 years) underwent Fraxel SR laser resurfacing and completed the survey. A total of 202 treatments (median, four; range, one to six) were performed. Seventy-five percent of all patients were very satisfied (4 or 5 rating) with treatment. Seventy-five percent with dyschromia, 74 percent with texture abnormalities, and 100 percent with scarring had a satisfaction score of 4 or 5. Multivariate analysis found scarring, four or more treatments, and age older than 56 years to be associated with a score of 4 or 5. The odds of giving a satisfaction score of 4 or 5 increased approximately two-fold for each additional treatment a patient received. CONCLUSIONS: This study reports the largest experience to date with the clinical use of the Fraxel SR laser and is the first report of patient satisfaction after fractional photothermolysis. Patients reported high satisfaction rates for improvements in texture, dyschromia, and scarring.

Interference of dimethyl alpha-(dimethoxyphosphinyl) p-chlorobenzyl phosphate (SR-202) in thyroid hormone metabolism: evidence of inhibition of monodeiodination.[Pubmed:3102663]

J Endocrinol. 1987 Jan;112(1):171-5.

SR-202 is a non-iodinated potential lipid-altering agent. When administered (100 mg) three times per day for 3 days to six euthyroid subjects it was associated with a 30 +/- 3% (mean +/- S.E.M.) fall in 3,3',5-triiodothyronine (T3) (P less than 0.001), a reciprocal 104 +/- 14% rise in 3,3',5'-tri-iodothyronine (reverse T3, rT3) (P less than 0.01), and a 37 +/- 7% rise in thyroxine (T4) (P less than 0.001). Basal and TRH-stimulated TSH did not change. These results suggested that SR-202 was acting as an inhibitor of the peripheral monodeiodination of T4 to T3. During a second study the same subjects received the same dose of SR-202 for a further 3 days following 15 days of progressive substitutive treatment with L-T4, which they continued to take at 200 micrograms/day until the end of the study. Despite higher levels of thyroid hormones in the substituted subjects, similar results were observed, serum T3 falling by 40 +/- 2% (P less than 0.001), serum rT3 and T4 rising by 168 +/- 24% (P less than 0.01) and 37 +/- 9% (P less than 0.01) respectively. These changes provide compelling evidence that SR-202 is an inhibitor of the peripheral conversion of T4 to T3 that acts on thyroid hormone metabolism without provoking a counter-regulatory pituitary response. It might prove to be a useful tool for the clinical investigation of thyroid function.

A new selective peroxisome proliferator-activated receptor gamma antagonist with antiobesity and antidiabetic activity.[Pubmed:12403851]

Mol Endocrinol. 2002 Nov;16(11):2628-44.

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) plays a key role in adipocyte differentiation and insulin sensitivity. Its synthetic ligands, the thiazolidinediones (TZD), are used as insulin sensitizers in the treatment of type 2 diabetes. These compounds induce both adipocyte differentiation in cell culture models and promote weight gain in rodents and humans. Here, we report on the identification of a new synthetic PPARgamma antagonist, the phosphonophosphate SR-202, which inhibits both TZD-stimulated recruitment of the coactivator steroid receptor coactivator-1 and TZD-induced transcriptional activity of the receptor. In cell culture, SR-202 efficiently antagonizes hormone- and TZD-induced adipocyte differentiation. In vivo, decreasing PPARgamma activity, either by treatment with SR-202 or by invalidation of one allele of the PPARgamma gene, leads to a reduction of both high fat diet-induced adipocyte hypertrophy and insulin resistance. These effects are accompanied by a smaller size of the adipocytes and a reduction of TNFalpha and leptin secretion. Treatment with SR-202 also dramatically improves insulin sensitivity in the diabetic ob/ob mice. Thus, although we cannot exclude that its actions involve additional signaling mechanisms, SR-202 represents a new selective PPARgamma antagonist that is effective both in vitro and in vivo. Because it yields both antiobesity and antidiabetic effects, SR-202 may be a lead for new compounds to be used in the treatment of obesity and type 2 diabetes.

gem-Diphosphonate and gem-phosphonate-phosphate compounds with specific high density lipoprotein inducing activity.[Pubmed:3612689]

J Med Chem. 1987 Aug;30(8):1426-33.

New diphosphonate compounds and related derivatives were synthesized and investigated for their activity in specifically inducing plasma high density lipoproteins (HDL) and high density lipoprotein cholesterol (HDL-C) in normal rats. The screening of numerous compounds has permitted the determination of the structural variations leading to optimal plasma lipid altering activity, indicating antiatherosclerotic potential. Among the compounds observed to be the most active, dimethyl alpha-(dimethoxyphosphinyl)-p-chlorobenzyl phosphate (20, SR-202, mifobate) was selected for further pharmacological and subsequent clinical development.

Mifobate (SR-202) is a potent and specific PPARγ antagonist. Mifobate (SR-202) selectively inhibits Thiazolidinedione (TZD)-induced PPARγ transcriptional activity (IC50=140 μM). Mifobate (SR-202) does not affect basal or ligand-stimulated transcriptional activity of PPARα, PPARβ, or the farnesoid X receptor (FXR). Mifobate (SR-202) shows antiobesity and antidiabetic effects.

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