The structure-activity relationships in two series of hypoglycemic benzoic acid derivatives (5, 6) were investigated. Series 5 resulted from meglitinide (3) when the 2-methoxy was replaced by an alkyleneimino residue. Maximum activity was observed with the cis-3, 5-dimethyl-piperidino (5h) and the octamethyleneimino (5l) residues. Series 6 resulted from the meglitinide analogon 4 bearing an inversed amido function when the 2-methoxy, the 5-fluoro, and the alpha-methyl residue were replaced by a 2-piperidino, a 5-hydrogen, and a larger alpha-alkyl residue, respectively. An alkoxy residue ortho to the carboxy group further increased activity and duration of action in the rat. The most active racemic compound, 6al (R4 = isobutyl; R = ethoxy), turned out to be 12 times more active than the sulfonylurea (SU) glibenclamide (1). Activity was found to reside predominantly in the (S)-enantiomers. Compared with the SUs 1 and 2 (glimepiride), the most active enantiomer, (S)-6al (AG-EE 623 ZW; repaglinide; ED50 = 10 micro/kg po), is 25 and 18 times more active. Repaglinide turned out to be a useful therapeutic for type 2 diabetic patients; approval was granted recently by the FDA and the EMEA. From investigations on the pharmacophoric groups in compounds of type 5 and 6, it was concluded that in addition to the two already known-the acidic group (COOH; SO2NH) and the amidic spacer (CONH; NHCO)-the ortho residue R1 (alkyleneimino; alkoxy; oxo) must be regarded as a third one. A general pharmacophore model suitable for hypoglycemic benzoic acid derivatives, SUs, and sulfonamides is proposed (Figure 6). Furthermore, from superpositions of low-energy conformations (LECs) of 1, 2, and (S)-6al, it was concluded that a common binding conformation (LEC II; Figure 10B) may exist and that differences in binding to the SU receptor and in the mechanism of insulin release between repaglinide and the two SUs may be due to specific hydrophobic differences.

1 Repaglinide, a novel compound with a nonsulphonylurea structure, is currently being clinically tested as a therapeutic agent. In the present study, the hypoglycaemic e ects of repaglinide in rats and dogs were investigated. 2 Whereas the R-enantiomer, AG-EE 624 ZW, showed only weak hypoglycaemic activity, the Senantiomer, repaglinide, turned out to be a potent hypoglycaemic compound in rats after oral as well as after intravenous administration. Only 50% of the dose of repaglinide was needed to be equie ective with the racemic mixture AG-EE 388 ZW. The corresponding ED50 values calculated for the e ects after 120 min p.a. (intravenous administration) were 3.4 mg kg 71 (repaglinide) and 6 mg kg 71 (AG-EE 388 ZW).3 When compared to glimepiride or glibenclamide, repaglinide displayed a 18 to 25 times higher potency in fasted rats. The ED50 values calculated for the e ects after 120 min p.a. (oral administration) were 10 mg kg 71 (repaglinide), 182 mg kg 71 (glimepiride) and 255 mg kg 71 (glibenclamide). 4 In glucose loaded rats (0.5, 1.0, 2.0 and 3.0 g kg 71 glucose, p.o.) repaglinide exerted a very strong antihyperglycaemic activity which was even more pronounced than under normoglycaemic conditions. So for a reduction in blood glucose of 1 mmol l 71 , 10.3, 9.3, 7.0 8.4 and 7.2 mg kg 71 repaglinide were needed after glucose loads of 0.0, 0.5, 1.0, 2.0 and 3.0 g kg 71 , respectively. 5 In beagle dogs repaglinide again showed a pronounced hypoglycaemic e ect (ED50 28.3 mg kg 71 ) which lasted for up to 24 h. However, insulin levels were only transiently increased. 6 The in vivo data presented are well supported by recently published in vitro ®ndings. From its activity pro®le, repaglinide appears to be a promising new therapeutic agent.

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