29112-55-8Relevant academic research and scientific papers
Use of a dipeptide chemical library in the development of non-peptide tachykinin NK3 receptor selective antagonists
Boden, Phil,Eden, Jon M.,Hodgson, Julie,Horwell, David C.,Hughes, John,McKnight, Alexander T.,Lewthwaite, Russell A.,Pritchard, Martyn C.,Raphy, Jenny,Meecham, Ken,Ratcliffe, Giles S.,Suman-Chauhan, Nirmala,Woodruff, Geoffrey N.
, p. 1664 - 1675 (2007/10/03)
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 binding assay resulted in the identification of Boc(S)Phe(S)PheNH2 (1), which has subsequently been developed, following a 'peptoid' design strategy, into a series of high-affinity NK3 receptor selective antagonists. The structure- activity relationship of the C-terminal portion of this dipeptide lead was first explored and led to the identification of the urea derivative Boc(S)Phe(R)αMePheNH(CH2)7NHCONH2 (41, PD157672). This modified dipeptide has a K(o) of 7 nM in blocking senktide-induced increases in intracellular calcium levels in human NK3 receptors stably expressed in CHO cells. Subsequent optimization of the N-terminal BocPhe group and the αMePhe residue side chain of 41 led to the identification of [S-(R*,S*)]-[2-(2,3- difluorophenyl)-1-methyl-1-[(7-ureidoheptyl)carbamoyl]ethyl]carbamic acid 2- methyl-1-phenylpropyl ester (60, PD161182), a non-peptide 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.
