Identification of a potent heterocyclic ligand to somatostatin receptor subtype 5 by the synthesis and screening of beta-turn mimetic libraries

Methods for the parallel synthesis of medium-ring heterocyclic beta-turn mi metics (1) are described, which enable the rapid preparation of libraries o f mimetics for the identification of small molecule ligands to receptors. T he generality of this method was first demonstrated by the rapid and high-y ielding synthesis of mimetics la-g that display a wide range of proteinogen ic amino acid side chains. Small molecule heterocyclic mimetics of the medi cinally important peptide somatostatin were then identified by the synthesi s of a focused library of beta-turn mimetics based upon the crucial Trp-Lys motif found in the turn region of somatostatin. Screening the library agai nst a panel of the five cloned human somatostatin receptors (hSST(1)-hSST(5 )) resulted in the identification of a potent small molecule ligand (Ih) wi th selectivity toward hSST(5), as well as potent ligands toward receptor su btypes 1-4, Furthermore, structure-activity relationships were used to esta blish the importance of each of the three diversity inputs present in compo und Ih. This investigation represents the first successful identification o f potent, small molecule ligands through the synthesis and evaluation of a focused library of turn mimetics (for one example of a successful screening effort of a nonfocused beta-turn library, see: Souers, A. J.; Virgilio, A. A.; Schurer, S.; Ellman, J. A.; Kogan, T. P.; West, H. E.; Ankener, W.; Va nderslice, P. Bioorg. Med. Chem. Lett. 1998, 8, 2297-2302). The results of the library screening revealed unexpected stereochemical and functional gro up preferences, reinforcing the critical importance of synthesizing and eva luating collections of mimetics as opposed to traditional iterative synthes is and evaluation approaches. The ability to prepare libraries of heterocyc lic turn mimetics that display three different side-chain inputs with multi ple distinct side-chain orientations should enable the rapid identification of small molecule heterocyclic ligands to a large number of receptor targe ts.