Repaglinide and Related Hypoglycemic Benzoic Acid Derivatives
journal contributionposted on 03.12.1998, 00:00 by Wolfgang Grell, Rudolf Hurnaus, Gerhart Griss, Robert Sauter, Eckhard Rupprecht, Michael Mark, Peter Luger, Herbert Nar, Helmut Wittneben, Peter Müller
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 α-methyl residue were replaced by a 2-piperidino, a 5-hydrogen, and a larger α-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 μg/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 knownthe 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 ). 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 B) 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.
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type 52 NHEMEACONHmeglitinide analogon 4inversed amido functionpharmacophore modelMaximum activityamidic spacerbenzoic acid derivativesRelated Hypoglycemic BenzoicNHCOalkyleneimino residueFDApharmacophoric groupsbinding conformationtype 2R 4Figure Balkoxy residue orthoZWinsulin releaseED 50series 6series 56 al18 timesCOOH12 times5 l5 hSUs 1SU receptorcarboxy groupracemic compoundLEC II