Repaglinide and related hypoglycemic benzoic acid derivatives

The structure-activity relationships in two series of hypoglycemic benzoic acid derivatives (5, 6) were investigated. Series 5 resulted from meglitini de (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 oc tamethyleneimino (5l) residues. Series 6 resulted from the meglitinide anal ogon 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 t o the carboxy group further increased activity and duration of action in th e rat. The most active racemic compound, 6al (R-4 = isobutyl; R = ethoxy), turned out to be 12 times more active than the sulfonylurea (SU) glibenclam ide (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 mu g/kg po), is 25 and 18 tim es 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 an d 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 R- 1 (alkyleneimino; alkoxy; ore) must be regarded as a third one. A general p harmacophore 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 th at a common binding conformation (LEC II; Figure 10B) may exist and that di fferences in binding to the SU receptor and in the mechanism of insulin rel ease between repaglinide and the two SUs may be due to specific hydrophobic differences.