Design, Synthesis, and SAR of Tachykinin Antagonists:  Modulation of Balance in NK₁/NK₂ Receptor Antagonist Activity

Abstract

Through optimization of compounds based on the dual NK(1)/NK(2) antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK(1) and NK(2) potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK(1) potency and thus afforded NK(1) preferential antagonists. Alterations of the piperidine region could then increase NK(2) potency to restore dual NK(1)/NK(2) selectivity. Through these efforts, three novel receptor antagonists from a single chemically related series were identified; two are dual NK(1)/NK(2) antagonists, and the third is an NK(1) preferential antagonist. In this paper, the factors affecting the balance of NK(1) and NK(2) selectivity in this series are discussed and the in vitro and in vivo properties of the novel antagonists are described.

Nonbiaryl and Heterobiaryl Atropisomers: Molecular Templates with Promise for Atropselective Chemical Transformations

“…142 When the R 1 was hydrogen, cyclization occurred exclusively on the N-acryloyl group leading to 268b. 178 However, if the R 1 substituent was a methyl group, cyclization occurred predominantly on the N-allyl substituent yielding 268a. Detailed kinetic study on the substrate that had o-methyl group revealed that the inherently fast N-acryloyl cyclization was retarded at least by 2 orders of magnitude.…”

Substance P: Structure, Function, and Therapeutics

“…Therefore simultaneous antagonism of both NK 1 and NK 2 receptors have been investigated, by altering the two key regions, piperidine and naphthamide moieties in the dual NK 1 /NK 2 receptor antagonist 45 (ZD-6021) [259]. Substitution at 2-naphthalene position increases NK 1 potency while alterations in piperidine region increases the NK 2 potency.…”

Total Synthesis and Structural Confirmation of the Antimalarial Naphthopyrone Lasionectrin

“…Attempts to effect carbonylation of the iodide to give ester 19 were unsuccessful using a variety of methods, with protodehalogenation predominantly occurring. Eventually, carbonylation was successfully achieved in a sealed tube at 120 °C under a carbon monoxide atmosphere in the presence of palladium acetate and triethylamine …”