Demonstration of the strength of focused combinatorial libraries in SAR optimisation of growth hormone secretagogues

A series of 96 growth hormone secretagogues, derived from ipamorelin are de scribed. The compounds are prepared as a 6 x 4 x 4 member library on solid support using a PAL resin. The compounds are all acylated dipeptides, based on two aromatic amino acids and a free amino N-terminal. All compounds are characterised by HPLC, LC-MS and their ability to release GH in a pituitar y cell based assay. The most potent compounds show EC50 values at 1 nM and are full agonists. We demonstrate the strength of focused combinatorial lib raries and confirm the pitfall in broad SAR exploration by giving examples where selected fragments obviously show poor receptor interaction except in very defined structural arrangements. (C) 1999 Editions scientifiques et m edicales Elsevier SAS.