Structure−Activity Relationships of 6-Methyl-benzo[b]thiophene-2-carboxylic Acid (1-{(S)-1-Benzyl-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]butylcarbamoyl}cyclopentyl)amide, Potent Antagonist of the Neurokinin-2 Receptor

Abstract

As part of a project aimed at the identification of a series of small, orally available antagonists for the hNK(2) receptor, starting from one of our capped dipeptide libraries, we succeeded in the chemical optimization of the first identified leads, finally producing a class of molecules with significant activity in our animal model after iv administration. We herein report the results of further chemical modifications made to reduce the overall peptide character of this series and the consequent improvement of their in vivo antagonist activity. The present work identified 6-methylbenzo[b]thiophene-2-carboxylic acid (1-[(S)-1-benzyl-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]butylcarbamoyl]cyclopentyl)amide (10i), endowed with subnanomolar potency in all the in vitro tests and being highly potent and of long duration upon in vivo testing after both iv and id dosing.

Synthesis, crystal structures, antiproliferative activities and reverse docking studies of eight novel Schiff bases derived from benzil

“…Though the obtained models exhibit only limited accuracy, it has been demonstrated that the modelled receptor pocket conformations can be validated or improved via docking of known ligands. For the Neurokinin 2 receptor, ligand 6-methylbenzo-[b]thiophene-2-carboxylic acid (1-{(S)-1-benzyl-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]butylcarbamoyl}cyclopentyl)amide (abbreviated as 10i in the original article) was used as the well-known antagonist with high affinity (Fattori et al, 2010). As for the 5-HT6 receptor, AVN-492, a new promising ligand (now tested in phase I trials) was selected (Ivachtchenko et al, 2017;Łażewska et al, 2019).…”

Applications of Chiral Squaramides: From Asymmetric Organocatalysis to Biologically Active Compounds

“…Squaramide C5, as the bifunctional aminocatalyst, involved an inverse-electron-demand hetero-Diels-Alder reaction to give the dihydropyran derivatives 21-22 in high enantioselectivity, which were the key intermediates to prepare natural-productrelevant tetrahydropyrans (Scheme 7). [18,19] In 2013, an organocatalytic domino sulfa-Michael/ Michael addition reaction between thiols and nitroolefin enoates was reported via a dynamic kinetic resolution strategy. [20] The chiral chromanes, with three contiguous stereocenters, were obtained in 88-98% yields, 5: 1-19: 1 drs, and 83-95% ee values (Scheme 8).…”

“…The tetrahydroxanthone structural unit is often found in nature and among pharmacologically active compounds. Squaramide C5 , as the bifunctional aminocatalyst, involved an inverse‐electron‐demand hetero‐Diels‐Alder reaction to give the dihydropyran derivatives 21 – 22 in high enantioselectivity, which were the key intermediates to prepare natural‐product‐relevant tetrahydropyrans (Scheme ) 18,19…”

A novel base-promoted cyclization: synthesis of substituted benzo[b]furans

“…1-4 For example, the benzofuran moiety is found in antidepressant (-)-BPAP, 5 angiotensin II inhibitors, 6 5-lipoxygenase inhibitors, 6 nerokinin-2 receptor antagonist, 7 cathepsin K inhibitors, 3 and calcium entry blockers. In addition, there are also many benzofuran-containing natural products including (−)-concentricolide, 8 (+)-frondosin B 9 and the eupomatenoid family.…”

“…Benzo [b]furan is an important structural scaffold in pharmaceutical research because compounds containing this moiety show a wide range of pharmacological activities. [1][2][3][4] For example, the benzofuran moiety is found in antidepressant (2)-BPAP, 5 angiotensin II inhibitors, 6 5-lipoxygenase inhibitors, 6 nerokinin-2 receptor antagonist, 7 cathepsin K inhibitors, 3 and calcium entry blockers. In addition, there are also many benzofurancontaining natural products including (2)-concentricolide, 8 (+)frondosin B 9 and the eupomatenoid family.…”