DISCOVERY OF LOW-MOLECULAR-WEIGHT ANTAGONISTS OF SUBSTANCE-P - RECENTDEVELOPMENTS AND PROSPECTS AS A THERAPEUTIC AGENT

The creation of antagonists of substance P (SP) has been the focus of intensive research because of their potential as therapeutic agents. A conventional for an SP antagonist is the synthesis of SP analogs in w hich amino acids are substituted or some peptide bonds are modified. A nother useful method is the screening of compounds from a sample file. This method, called random screening, led to the discovery of novel a nd potent non-peptide antagonists. Apart from these two strategies, we were able to design low-molecular weight antagonists from a known pep tide lead. The search for the essential part for receptor binding, imp rovement of the stability against enzymatic metabolism, and chemical m odifications led to a potent tripeptide (4, FR 113680). The molecular size of this tripeptide was reduced to a dipeptide structure such as 1 3, through newly designed branched tripeptides (5-10). Further optimiz ation of the lysine part of 13 into (2 S, 4 R) Hyp and subsequent modi fication of the side chain parts culminated in the potent dipeptide an tagonist (15, FK 888). The pharmacological profile of 15 as an antiast hma agent is also presented.