A combinatorial approach toward the discovery of non-peptide, subtype-selective somatostatin receptor ligands

The tetradecapeptide somatostatin is widely distributed throughout the body and is thought to be involved with a variety of regulatory functions. Rece ntly, five human somatostatin receptors (hSSTR1-5) have been cloned and cha racterized. Several selective peptidal agonists of the hSSTR receptors are known, and we sought to apply this information to the design of novel non-p eptide small molecule ligands for each receptor. Initial computational meth ods identified a 200 nM murine SSTR2 active compound via a database search of our sample collection. A combinatorial library was designed around the s tructural class of the compound with the goal of rapidly developing this in itial lead into the desired subtype-selective small molecules in order to c haracterize the pharmacology of each of the receptor subtypes. The library was synthesized using the resin-archive, iterative deconvolution format. Th e total number of unique compounds in the library was expected to be 131 67 0, present in 79 mixtures of 1330 or 2660 compounds per mixture. Through se quences of screening and mixture deconvolution, the components of selective and highly active (K-i = 50 pM to 200 nM) non-peptide small molecule ligan ds for somatostatin subtypes 1, 2, 4, and 5 were identified. In addition to discovering compounds with the desired activity and selectivity, useful st ructure/activity information was generated which can be used in the design of new compounds and second-generation combinatorial libraries.