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

Abstract

In connection with a program directed at potent and balanced dual NK 1 /NK 3 receptor ligands, a focused exploration of an original class of peptidomimetic derivatives was performed. The rational design and molecular hybridization of a novel phenylalanine core series was achieved to maximize the in vitro affinity and antagonism at both human NK 1 and NK 3 receptors. This study led to the identification of a new potent dual NK 1 /NK 3 antagonist with pK i values of 8.6 and 8.1, respectively.

Advances in the Synthesis of Benzo‐Fused Spiro Nitrogen Heterocycles: New Approaches and Modification of Old Strategies

“…[299] The obtained compound 317 showed activity as a new potent dual NK 1 /NK 3 (neurokinin 1 and neurokinin 3) antagonist with pK i values of 8.6 and 8.1, respectively. [300] Performance index of this compound in relation to neurokinin 3 is better than the similar data of the previously synthesized NK 3 R antagonist, compound 319 ( Figure 2). [301] Both NK 1 and NK 3 receptors are localized in the corticolimbic structures of the brain.…”

Enantioselective Total Synthesis of (−)‐Hosieine A

“…Our initial proposal to perform a hydroboration under numerous reaction conditions were discouraging (Table 1, entries 1–3) 14. Radical bromination conditions adopted from the literature only gave dibromo adducts (entry 4),19 which were inert to any attempts at pyridone installation. Although epoxidation with in situ generated DMDO could afford two inseparable stereoisomers (d.r.…”

Synthesis and Fungicidal Activity of 1-(Carbamoylmethyl)-2-aryl-3,1-benzoxazines

“…3,1-Benzoxazine derivatives show anticonvulsant [ 1 ], herbicidal [ 2 ], fungicidal [ 3 , 4 ], and anticancer activity [ 5 ], and some are potent progesterone receptor (PR) agonists [ 6 ] or DNA-binding antitumor agents [ 7 ]. 3,1-Benzoxazinones exhibit antihypertensive [ 8 ] and antiproliferative activities [ 9 ], or are potent PR agonists/antagonists [ 10 , 11 ], potent human leukocyte elastase inhibitors [ 12 ], serine protease inhibitors [ 13 , 14 , 15 ], long chain fatty acid elongase 6 inhibitors [ 16 ], NK 1 /NK 3 receptor antagonists [ 17 ], α-chymotrypsin inhibitors [ 18 ], mineralocorticoid receptors antagonists [ 19 ], and are even used as anti-HIV-1 reverse transcriptase inhibitors [ 20 , 21 ]. Therefore, the synthesis of 3,1-benzoxazines and 3,1-benzoxazinone has attracted considerable interest.…”