Andrew B. McElroy

GR159897 and related analogues as highly potent, orally active non-peptide neurokinin NK2 receptor antagonists.

Abstract Optimisation of NK 2 receptor affinity in a series of sulfur derivatives resulted in the identification of Highly potent 5-fluoroindol-3-ylethyl[4-(phenylsulfinyl methyl])piperidines. Further structure activity analysis led to GR 159897 an NK 2 receptor antagonist which potently blocks agonist-induced bronchoconstriction in the guinea-pig when administered by peripheral and oral routes.

Low molecular weight neurokinin NK2 antagonists

Abstract A deletion - optimization strategy based on an initial heptapeptide lead structure 1 led to potent and selective neurokinin NK2 antagonists 5 (pKB=9.3) and 9 (pKB=7.9) of substantially reduced molecular size. Tetrapeptide 5 (0.1 μmol/Kg i.v.) potently inhibits NK2 agonist-induced bronchoconstriction in guinea-pigs. Whilst less potent than 5 in vivo, the dipeptoid 9 (5 μmol/Kg i.v.) had a significantly longer biological half-life (> 2 h), and provides a potential lead towards non-peptide analogues.