Methods for the parallel synthesis of medium-ring heterocyclic
-turn mimetics (
1) are described,which enable the rapid preparation of libraries of mimetics for the identification of small molecule ligands toreceptors. The generality of this method was first demonstrated by the rapid and high-yielding synthesis ofmimetics
1a-g that display a wide range of proteinogenic amino acid side chains. Small molecule heterocyclicmimetics of the medicinally important peptide somatostatin were then identified by the synthesis of a focusedlibrary of
-turn mimetics based upon the crucial Trp-Lys motif found in the turn region of somatostatin.Screening the library against a panel of the five cloned human somatostatin receptors (hSST
1-hSST
5) resultedin the identification of a potent small molecule ligand (
1h) with selectivity toward hSST
5, as well as potentligands toward receptor subtypes 1-4. Furthermore, structure-activity relationships were used to establishthe importance of each of the three diversity inputs present in compound
1h. This investigation represents thefirst successful identification of potent, small molecule ligands through the synthesis and evaluation of a
focusedlibrary of turn mimetics (for one example of a successful screening effort of a nonfocused
-turn library, see:Souers, A. J.; Virgilio, A. A.; Schürer, S.; Ellman, J. A.; Kogan, T. P.; West, H. E.; Ankener, W.; Vanderslice,P.
Bioorg. Med. Chem. Lett. 1998,
8, 2297-2302). The results of the library screening revealed unexpectedstereochemical and functional group preferences, reinforcing the critical importance of synthesizing andevaluating collections of mimetics as opposed to traditional iterative synthesis and evaluation approaches. Theability to prepare libraries of heterocyclic turn mimetics that display three different side-chain inputs withmultiple distinct side-chain orientations should enable the rapid identification of small molecule heterocyclicligands to a large number of receptor targets.
