Identification of novel NK1/NK3 dual antagonists for the potential treatment of schizophrenia

Identification of a Crucial Amino Acid in the Helix Position 6.51 of Human Tachykinin Neurokinin 1 and 3 Receptors Contributing to the Insurmountable Mode of Antagonism by Dual NK1/NK3 Antagonists

“…In this context, it is interesting to note that compound 17a (GSK), which exhibited an insurmountable mode of antagonism at NK 1 /NK 3 , also contains a −CH 2 OH group, just like compound 5. 29 To further test the importance of the −CH 2 OH group, we also included compounds 7, 8, 9, 10, and 11 in our study. As expected, the −CH 2 OH substituted compound 7 was also insurmountable at hNK 3 while compounds 8, 10, and 11 lacking this functional group displayed a surmountable mode of antagonism.…”

“…Compound 17a was reported to have a high potency at NK 1 (K i = 0.06 nM) and NK 3 (K i = 1 nM), as measured in a functional cell-based assay, and also displayed an insurmountable profile of antagonism at both NK 1 and NK 3 . 29 The objective of the current study was to elucidate the molecular interaction between human NK 1 /NK 3 and compound 5, which is involved in the slow kinetics and insurmountable behavior at both receptors. Using site-directed mutagenesis, rhodopsin-based hNK 1 and hNK 3 modeling, and functional [ 3 H]IP accumulation assay, we have identified a single amino acid in the helix position 6.51 of both NK 1 and NK 3 as a crucial residue that determines the insurmountable behavior of compound 5.…”

“…Recently, researchers at GSK have reported novel dual NK 1 /NK 3 antagonists based on a similar pyridine scaffold as compound 5 . , Interestingly, among these compounds, 2-[3,5-bis­(trifluoromethyl)­phenyl]- N -{4-(4-fluoro-2-methylphenyl)-6-[(4-(hydroxymethyl)-1-methyl-5-oxo-3-pyrrolidinyl]-3-pyridinyl}- N ,2-dimethylpropanamide (enantiomer 2) (GSK, “compound 17a ”) , has a high structural similarity to compound 5 and differs only in the pyrrolidine substituent (Figure ). Compound 17a was reported to have a high potency at NK 1 ( K i = 0.06 nM) and NK 3 ( K i = 1 nM), as measured in a functional cell-based assay, and also displayed an insurmountable profile of antagonism at both NK 1 and NK 3 …”

Diastereoselective radical addition to γ-alkyl-α-methylene-γ-butyrolactams and the synthesis of a chiral pyroglutamic acid derivative

“…γ-Lactams exist in many natural products and biologically active compounds and are one of the most important classes of compounds for drug discovery [1–3]. Substituted γ-lactams, in particular, have potential application in drug synthesis, but the development of stereoselective synthesis of chiral γ-lactams remains a challenge [4–5].…”

Design, Synthesis, and Optimization of Balanced Dual NK1/NK3 Receptor Antagonists

“…In this context, we turned our attention to the known α-aryl acetamide derivatives 3 and 4 as potent and selective NK1 receptor antagonists. − Both series are structurally related with a common 3,4-dichlorophenyl acetic acid unit, either mono- or disubstituted at the benzylic position, linked via an alkyl spacer to a piperidinyl or spiropiperidinyl motif. We hypothesized that the combination of this moiety with our previously identified N -(2-aminoethyl)phenylalanine pharmacophore, tethered by a 3,4-dichlorophenyl acetyl unit, could produce a new hybrid compound 2 with potentially improved and balanced affinity for the NK 1 and NK 3 receptors (Figure ).…”