in humans by 33%, has re-invigorated this area of research (32,33). Recent reports describe receptor specific carbazole ureas 13 and orally available, brain-penetrable arylpyrazole 14 for the treatment of obesity. A non-orally available NPY-Y5 specific compound (GW438014A) has been reported to decrease the rate of weight gain and reduce fat mass by (10 mg/kg) intraperitoneal administration 15 BID (34-36).
Protein Tyrosine Phosphatase 1B - Another active area for anti-obesity research has been the use of protein tyrosine phosphatase 1B (PTP1B) inhibitors for the treatment of obesity and diabetes. (38). PTP1B is involved in down-regulation of receptor tyrosine kinase activity following stimulation of the insulin or leptin receptors. In theory, inhibition of this pathway should ameliorate the insulin/leptin de-sensitization often seen in obese patents. In addition, increased insulin sensitivity and resistance to diet induce obesity was seen in PTP1B knockout mice (39). Recent reports have described the synthesis of selective 1,2-Napthoquinone inhibitors 16, non-competitive Pyridazine inhibitors 17, competitive [Difluoro-(3-alkenylphenyl)-methyl]-phosphonic acids 18 and orally available derivatives of 2-(oxaylamno)benzoic acid 19 as potent PTP1B inhibitors (40-43).
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