Spiro[pyrrolidine-3,3′-oxindoles] and Their Indoline Analogues as New 5-HT6 Receptor Chemotypes

Abstract

Synthetic derivatives of spiro[pyrrolidinyl-3,3′-oxindole] alkaloids (coerulescine analogues) were investigated as new ligands for aminergic G-protein coupled receptors (GPCRs). The chemical starting point 2′-phenylspiro[indoline-3,3′-pyrrolidin]-2-one scaffold was identified by virtual fragment screening utilizing ligand- and structure based methods. As a part of the hit-to-lead optimization a structure-activity relationship analysis was performed to explore the differently substituted 2′-phenyl-derivatives, introducing the phenylsulphonyl pharmacophore and examining the corresponding reduced spiro[pyrrolidine-3,3′-indoline] scaffold. The optimization process led to ligands with submicromolar affinities towards the 5-HT6 receptor that might serve as viable leads for further optimization.

The 1,3,5-Triazine Derivatives as Innovative Chemical Family of 5-HT6 Serotonin Receptor Agents with Therapeutic Perspectives for Cognitive Impairment

“…The state of art in 2014 indicated that more than 40% of the 5-HT 6 R ligands include indole moieties and more than 80% sulfone ones [12]. This situation has not been significantly changed for the last 4 years [13,14,15,16]. Nevertheless, this huge structurally-similar family has provided a number of compounds with therapeutic perspectives, especially promising for antagonists as potential agents useful in therapy of Alzheimer’s disease.…”

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

“…Among 17 antagonists that have reached clinical trials, only one non-sulfonyl and non-indole structure (1, Figure 1) can be found [4,7,10]. The situation has not been improved during last four years, providing new active compounds among 1H-pyrrolo [3,2-c]quinolones (2) [11], N1-azinylsulfonyl-1H-indoles (3) [12], spiro[pyrrolidine-3,3 -oxindoles] (4) [13] and tricyclic pyrano [2,3,4-cd]indoles (5) [14] (Figure 1), thus indicating a strong need to extend the chemical space of 5-HT 6 R ligands. Molecules 2019, 24, x; doi: www.mdpi.com/journal/molecules Serotonin receptors 5-HT6 (5-HT6Rs) seem to be the most intriguing among the members of 5-HTRs family and also highly promising as a target for innovative therapy of CNS (central nervous system)-diseases.…”

“…The situation has not been improved during last four years, providing new active compounds among 1Hpyrrolo [3,2-c]quinolones (2) [11], N1-azinylsulfonyl-1H-indoles (3) [12], spiro[pyrrolidine-3,3′oxindoles] (4) [13] and tricyclic pyrano [2,3,4-cd]indoles (5) [14] (Figure 1), thus indicating a strong need to extend the chemical space of 5-HT6R ligands. Predominant sulfone-and indole-containing structures of serotonin receptors 5-HT6 (5-HT6R) ligands found previously: the only one non-sulfonyl and non-indole structure in clinical trials (1) [4]; the most active 5-HT6R agents that represent the chemical families recently found in primary screenings, i.e., 1H-pyrrolo [3,2-c]quinolones (2) [11], N1-azinylsulfonyl-1H-indoles (3) [12], spiro[pyrrolidine-3,3′-oxindoles] (4) [13] and tricyclic pyrano [2,3,4-cd]indoles (5) [14]; the most advanced compounds in clinical trials towards Alzheimer's disease (AD), i.e., Idalopirdine (6), Intepirdine (7) and [15]. (5-HT 6 R) ligands found previously: the only one non-sulfonyl and non-indole structure in clinical trials (1) [4]; the most active 5-HT 6 R agents that represent the chemical families recently found in primary screenings, i.e., 1H-pyrrolo [3,2-c]quinolones (2) [11], N1-azinylsulfonyl-1H-indoles (3) [12], spiro[pyrrolidine-3,3 -oxindoles] (4) [13] and tricyclic pyrano [2,3,4-cd]indoles (5) [14]; the most advanced compounds in clinical trials towards Alzheimer's disease (AD), i.e., Idalopirdine (6), Intepirdine (7) and [15].…”

Fragment-to-Lead Medicinal Chemistry Publications in 2017

“…Articles from 2017 reporting the continued progression of a fragment-derived series, where the potency/affinity criteria were already met in an article published before 2017, have not been included. In applying these criteria, we have inevitably excluded some high quality articles, particularly those focusing on challenging biological targets. − …”

“…Figure 2 shows the distribution of target classes for the 2017 examples, as well as those from 2015 and 2016. There was a pronounced increase in the number of articles describing the development of antagonists of PPIs for 2017 (11 articles) when compared to 2016 (4) or 2015 (5). In particular, 6 campaigns were targeted against bromodomains, leading us to consider this as a separate subclass of PPIs.…”