N-Benzoyl-DL-phenylalanine (1) was found to possess hypoglycemic activity. A series of the analogues of compound 1 were prepared and evaluated for their blood glucose lowering activity. Both the steric effects of the phenylalanine moiety and the effects of variations in the acyl moiety were investigated. This study elucidated some of the structure-activity relationships and led to the development of N-(4-ethylbenzoyl)-D-phenylalanine (34), which was 50 times more potent than the initial compound 1.

. Combination therapy with PPAR␥ and PPAR␣ agonists increases glucose-stimulated insulin secretion in db/db mice. Am J Physiol Endocrinol Metab 284: E966-E971, 2003; 10.1152/ ajpendo.00149.2002.-Although peroxisome proliferator-activated receptor (PPAR)␥ agonists ameliorate insulin resistance, they sometimes cause body weight gain, and the effect of PPAR agonists on insulin secretion is unclear. We evaluated the effects of combination therapy with a PPAR␥ agonist, pioglitazone, and a PPAR␣ agonist, bezafibrate, and a dual agonist, KRP-297, for 4 wk in male C57BL/6J mice and db/db mice, and we investigated glucose-stimulated insulin secretion (GSIS) by in situ pancreatic perfusion. Body weight gain in db/db mice was less with KRP-297 treatment than with pioglitazone or pioglitazone ϩ bezafibrate treatment. Plasma glucose, insulin, triglyceride, and nonesterified fatty acid levels were elevated in untreated db/db mice compared with untreated C57BL/6J mice, and these parameters were significantly ameliorated in the PPAR␥ agonist-treated groups. Also, PPAR␥ agonists ameliorated the diminished GSIS and insulin content, and they preserved insulin and GLUT2 staining in db/db mice. GSIS was further increased by PPAR␥ and -␣ agonists. We conclude that combination therapy with PPAR␥ and PPAR␣ agonists may be more useful with respect to body weight and pancreatic GSIS in type 2 diabetes with obesity.peroxisome proliferator-activated receptor; glucose-stimulated insulin secretion; glucolipotoxicity; insulin resistance; type 2 diabetes with obesity PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)␥ agonists have been used for the treatment of type 2 diabetic patients, especially those with obesity, all over the world. They ameliorate insulin resistance of peripheral tissues, such as skeletal muscle, liver, and adipocytes, by various suggested mechanisms. Although some literature has suggested effects of PPAR␥ agonists on the pancreas (13, 32), only a few studies have investigated this issue (23,29,30). Because the expression of PPAR␥ is confirmed not only in rodent (1) but also in human islets (5), an effect of PPAR␥ agonists on the pancreas has been suggested.On the other hand, fibrates are PPAR␣ agonists and have been used for patients with dyslipidemia. Some literature has reported that PPAR␣ agonists also ameliorated insulin resistance (6,7,14,19,24,28,36), but the effect on insulin secretion is unclear. Dual agonists of PPAR␥ and -␣, 25,26) and , have been developed, and their utility for diabetes and/or metabolic syndrome has been suggested. However, studies of combination therapy with a PPAR␥ agonist and a PPAR␣ agonist are rare (2, 21), and their effect on insulin secretion has not been reported.We hypothesized that combination therapy with PPAR␥ and -␣ agonists would be useful for reducing lipotoxicity (10, 20, 37) in type 2 diabetes with obesity by augmenting the lipid-lowering effects. We used the PPAR␥ agonist pioglitazone (PIO), combination therapy with the PPAR␥ agonist PIO and the PPAR␣ agonist bezabibrate (P...

A series of analogues of N-(cyclohexylcarbonyl)-D-phenylalanine (5) have been synthesized and evaluated for their hypoglycemic activity. Relationships were studied between the activity and the three-dimensional structure of the acyl moiety, which was characterized by high-resolution 1H NMR spectroscopy and MNDO calculations. The role of the carboxyl group of the phenylalanine moiety was also studied by comparing the activities of the enantiomers, the decarboxyl derivative, the esters, and the amides of the phenylalanine derivatives. Thus, the structural requirements for possessing hypoglycemic activity was elucidated and a highly active compound, N-[(trans-4-isopropylcyclohexyl)carbonyl]-D-phenylalanine (13) was obtained, which showed a 20% blood glucose decrease at an oral dose of 1.6 mg/kg in fasted normal mice.

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