Disease relevance of (2S)-4-[(3aS,7aR)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-2-benzyl-4-oxo-butanoic acid

• Absence of exacerbation of myocardial stunning in anesthetized dogs treated with KAD-1229, a novel hypoglycemic agent [1].
• The effects exerted by KAD-1229 on the post-prandial plasma glucose rise in STZ-induced mild NIDDM (mNIDDM) rats were different from those of sulfonylureas [2].
• We also tested the efficacy of KAD-1229 in more severe STZ-induced NIDDM (sNIDDM) rats to elucidate the effects of the drug on the long-term glycemic controls and diabetic complications [2].
• In this model, KAD-1229 reduced the increase in plasma glucose level without producing hypoglycemia [3].
• The results suggest that in type 2 diabetes caused by, at least, insulin deficiency, KAD-1229 may improve impaired insulin secretion in the early phase and attenuate hyperglycemia without causing a sustained hypoglycemia [3].

High impact information on (2S)-4-[(3aS,7aR)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-2-benzyl-4-oxo-butanoic acid

• 5. When glucagon release was stimulated with 2.8 mM glucose, KAD-1229 inhibited this hypoglycaemia-induced glucagon secretion [4].
• Effect of a non-sulphonylurea hypoglycaemic agent, KAD-1229 on hormone secretion in the isolated perfused pancreas of the rat [4].
• Further, the insulin and somatostatin responses to KAD-1229 were largely attenuated [4].
• In vitro insulinotropic action of a new non-sulfonylurea hypoglycemic agent, calcium (2s)-2-benzyl-3-(cis-hexahydro-2-isoindolinyl-carbonyl) propionate dihydrate (KAD-1229), in rat pancreatic B-cells [5].
• Novel rapid- and short-acting hypoglycemic agent, a calcium(2s)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionate (KAD-1229) that acts on the sulfonylurea receptor: comparison of effects between KAD-1229 and gliclazide [6].

Chemical compound and disease context of (2S)-4-[(3aS,7aR)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-2-benzyl-4-oxo-butanoic acid

• Even though their hypoglycemic effects were of similar magnitude, glibenclamide (1 mg/kg, i.v.), but not KAD-1229, exacerbated the myocardial stunning induced by occlusion/reperfusion of the descending coronary artery [1].
• Our aim was to establish a diabetes mellitus model in dogs, and then during an oral glucose tolerance test to compare the hypoglycemic effect and insulinotropic action of KAD-1229, a new hypoglycemic agent, with that of gliclazide, a conventional sulfonylurea [3].
• A rapid- and short-acting hypoglycemic agent KAD-1229 improves post-prandial hyperglycemia and diabetic complications in streptozotocin-induced non-insulin-dependent diabetes mellitus rats [2].

Biological context of (2S)-4-[(3aS,7aR)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-2-benzyl-4-oxo-butanoic acid

• KAD-1229 stimulated insulin release from hamster's insulin-oma cell line, HIT T15 cells, at a concentration from 10(-8) M to 10(-5) M and inhibited 86Rb+ efflux from these cells with IC50 of 8.4 x 10(-9) M [6].
• When membrane potential was monitored by a perforated mode of patch clamp, KAD-1229 induced depolarization of plasma membrane, which was followed by a burst of action potentials [7].
• KAD-1229 also stimulated the oxidation of [2-14C]-pyruvate and [6-14C]-glucose in the tricarboxylic acid cycle (+18 and +31%, respectively), indicating that stimulation of tricarboxylic acid cycle activity and/or enhancement of the glycolytic flux rate had occurred [8].
• In the presence of 10 mM glucose, KAD-1229 increased the L-lactate production (41.1 +/- 0.9 versus 60.9 +/- 2.6 mumol of lactate/g of cells/30 min; P < 0.05) and inhibited gluconeogenesis in hepatocytes (0.94 +/- 0.02 versus 0.70 +/- 0.03 mumol of [2-14C]-pyruvate converted to glucose/g of cells/20 min; P < 0.05) [8].

Anatomical context of (2S)-4-[(3aS,7aR)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-2-benzyl-4-oxo-butanoic acid

• In a receptor-binding experiment, unlabeled glibenclamide completely inhibited [(3)H]glibenclamide binding to the myocardium, but KAD-1229 did not [1].
• 3. It is speculated that the ionophoretic property of KAD-1229 might participate to the remodelling of cationic fluxes evoked by this insulinotropic agent in pancreatic islet cells [9].

Associations of (2S)-4-[(3aS,7aR)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-2-benzyl-4-oxo-butanoic acid with other chemical compounds

• Mitiglinide (KAD-1229), a new anti-diabetic drug, is thought to stimulate insulin secretion by closing the ATP-sensitive K+ (K(ATP)) channels in pancreatic beta-cells [10].
• At normal extracellular K+ concentration (5 mM), the meglitinide analogues A-4166, KAD-1229, repaglinide and S3075, all tested at a 10 mu M concentration, markedly enhanced insulin release evoked by 6 mM D-glucose in isolated rat pancreatic islets [11].
• Four novel non-sulfonylurea insulin secretagogues are in advanced clinical development: A-4166, KAD-1229, BTS 67 582 and repaglinide [12].

Gene context of (2S)-4-[(3aS,7aR)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-2-benzyl-4-oxo-butanoic acid

• 7. We conclude that KAD-1229 stimulates insulin and somatostatin release, while it inhibits glucagon release following transient stimulation [4].
• We have investigated the hypoglycemic effects of the newly synthesized short-acting nonsulphonylurea hypoglycemic agent calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)-propionate dihydrate (KAD-1229) in non-insulin-dependent diabetes mellitus (NIDDM) rats [13].
• The two shortest-acting compounds, A-4166 and KAD-1229, will be developed to be taken prior to each main meal, while the slower, longer duration agents, repaglinide and BTS 67 582, may be developed to be taken twice daily [12].

Analytical, diagnostic and therapeutic context of (2S)-4-[(3aS,7aR)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-2-benzyl-4-oxo-butanoic acid

• In inside out configuration of patch-clamp technique, KAD-1229 attenuated the opening of ATP-sensitive K+ channels [7].
• NIDDM rats that were given a neonatal injection of 60 mg/kg streptozotocin showed a dose-dependent but attenuated response to oral administration of KAD-1229 and gliclazide, and their impaired glucose tolerance was improved but not normalized [13].

References