USE OF A DIPEPTIDE CHEMICAL LIBRARY IN THE DEVELOPMENT OF NONPEPTIDE TACHYKININ NK3 RECEPTOR-SELECTIVE ANTAGONISTS

The use of a dipeptide library as the source of a micromolar chemical lead compound for the human tachykinin NK3 receptor is described. The screening of a dipeptide library through a cloned human NK3 receptor b inding assay resulted in the identification of Boc(S)Phe(S)PheNH(2) (1 ), which has subsequently been developed, following a 'peptoid' design strategy, into a series of high-affinity NK3 receptor selective antag onists. The structure-activity relationship of the C-terminal portion of this dipeptide lead was first explored and led to the identificatio n of the urea derivative Boc(S)Phe(R)alpha MePheNH(CH2)(7)NHCONH2 (41, PD157672). This modified dipeptide has a K-e of 7 nM in blocking senk tide-induced increases in intracellular calcium levels in human NK3 re ceptors stably expressed in CHO cells. Subsequent optimization of the N-terminal BocPhe group and the alpha MePhe residue side chain of 41 l ed to the identification of methyl-1-[(7-ureidoheptyl)carbamoyl]ethyl] carbamic acid 2-methyl-1-phenylpropyl ester (60, PD161182), a non-pept ide NK3 receptor selective antagonist. Compound 60 blocks the senktide -evoked increases in intracellular calcium levels in cloned human NK3 receptors stably expressed in CHO cells with K-e of 0.9 nM.