Moving out of CF3‐Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF5) Group

Author:

Witoszka Katarzyna1ORCID,Matalińska Joanna1ORCID,Misicka Aleksandra12ORCID,Lipiński Piotr F. J.1ORCID

Affiliation:

1. Department of Neuropeptides Mossakowski Medical Research Institute Polish Academy of Sciences Pawińskiego 5 02-106 Warsaw Poland

2. Faculty of Chemistry University of Warsaw Pasteura 1 02-093 Warsaw Poland

Abstract

AbstractThe NK1 receptor (NK1R) is a molecular target for both approved and experimental drugs intended for a variety of conditions, including emesis, pain, and cancers. While contemplating modifications to the typical NK1R pharmacophore, we wondered whether the CF3 groups common for many NK1R ligands, could be replaced with some other moiety. Our attention was drawn by the SF5 group, and so we designed, synthesized, and tested ten novel SF5‐containing compounds for NK1R affinity. All analogues exhibit detectable NK1R binding, with the best of them, compound 5 a, (3‐bromo‐5‐(pentafluoro‐λ6‐sulfanyl)benzyl acetyl‐L‐tryptophanate) binding only slightly worse (IC50=34.3 nM) than the approved NK1R‐targeting drug, aprepitant (IC50=27.7 nM). Molecular docking provided structural explanation of SAR. According to our analysis, the SF5 group in our compounds occupies a position similar to that of one of the CF3 groups of aprepitant as found in the crystal structure. Additionally, we checked whether the docking scoring function or energies derived from Fragment Molecular Orbital quantum chemical calculations may be helpful in explaining and predicting the experimental receptor affinities for our analogues. Both these methods produce moderately good results. Overall, this is the first demonstration of the utility of the SF5 group in the design of NK1R ligands.

Publisher

Wiley

Subject

Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology

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