1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists

Micheli, Fabrizio; Bernardelli, Andrea; Bianchi, Federica; Braggio, Simone; Castelletti, Laura; Cavallini, Palmina; Cavanni, Paolo; Cremonesi, Susanna; Cin, Michele Dal; Feriani, Aldo; Oliosi, Beatrice; Semeraro, Teresa; Tarsi, Luca; Tomelleri, Silvia; Wong, Andrea; Visentini, Filippo; Zonzini, Laura; Heidbreder, Christian

doi:10.1016/j.bmc.2016.02.031

Cited by 18 publications

(31 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The second series of compounds which attracted the interest of researchers were the 1,2,4‐triazolyl‐octahydropyrrolo[2,3‐ b ]pyrroles . Examples of these compounds are shown in Figure .…”

Section: New Scaffoldsmentioning

confidence: 99%

“…Examples of these compounds are shown in Figure . At the top, two generic structures show the main areas of medicinal chemistry exploration reported in the original manuscript . Considering that the aryl octahydropyrrolo[2,3‐ b ]pyrrole template contains two stereogenic centers, the racemate was submitted for testing, and in the case of interesting results, each single enantiomer was also tested after chromatographic separation.…”

Section: New Scaffoldsmentioning

confidence: 99%

“…The SAR exploration started on the aryl ring attached to the bicyclic system, showing the influence of aryl functionalization both on selectivity versus the DA D 2 receptor and against the hERG channel. Although sub‐nanomolar potency was observed (p K i =9.4) with 3,5‐dichloro substitution (compound #13 in Table 1 of reference ), the affinity at the hERG channel also increased to unacceptable values (pIC 50 >7) showing that the increased lipophilicity was detrimental for further development of the molecule.…”

Section: New Scaffoldsmentioning

confidence: 99%

“…Exploration continued with replacement of the oxazole ring by 2‐pyrazine (compound 18 , Figure and Table 2 in reference , compound #18), and once again sub‐nanomolar affinity at the D 3 R (p K i =9.7) was observed, but affinity for hERG was still high (pIC 50 >7). Nonetheless, the ability to replace such a scaffold with alternative heterocyclic groups, either aromatic or nonaromatic, allowed manipulation of the compound′s overall lipophilicity.…”

Section: New Scaffoldsmentioning

confidence: 99%

See 3 more Smart Citations

Novel, Selective, and Developable Dopamine D₃ Antagonists with a Modified “Amino” Region

Micheli

2017

ChemMedChem

Self Cite

View full text Add to dashboard Cite

This Minireview describes a presentation made at the XXIV National Meeting in Medicinal Chemistry (NMMC) held in Perugia (Italy), September 11–14, 2016. It relates to the discovery of novel templates of the so‐called “amino” region of dopamine D3 receptor antagonists. Moving from the early scaffolds, which were modified in the amine portion, this review discusses the variations that led to the discovery of new systems published in 2016, which allowed the identification of compounds endowed with great selectivity over the dopamine D2 receptor and the human ether‐à‐go‐go‐related gene (hERG) ion channel. The main efforts in characterizing these compounds were devoted not only to determining their potency and selectivity relative to closely associated targets (e.g., the dopamine D2 receptor), but to ensure a large therapeutic window versus liability points such as hERG. In particular, we present examples of derivatives with selectivities greater than 2000‐fold. Furthermore, much focus is devoted to the overall developability of the scaffolds, ensuring that appropriate physicochemical and pharmacokinetic parameters are present in all compounds progressing through the screening cascade.

show abstract

Section: New Scaffoldsmentioning

confidence: 99%

Section: New Scaffoldsmentioning

confidence: 99%

Section: New Scaffoldsmentioning

confidence: 99%

Section: New Scaffoldsmentioning

confidence: 99%

See 2 more Smart Citations

Novel, Selective, and Developable Dopamine D₃ Antagonists with a Modified “Amino” Region

Micheli

2017

ChemMedChem

Self Cite

View full text Add to dashboard Cite

show abstract

“…1, 11, 20 GlaxoSmithKline (GSK) disclosed several 1,2,4-triazole-based compounds with excellent D 3 R affinity and selectivity profiles, 21–23 most notably, GSK598,809 ( 4 ), the first D 3 R selective antagonist to exhibit clinical evidence as a potential therapeutic for substance abuse disorders. 24 More recently, Micheli and co-workers reported a D 3 R antagonist with an azaspiro alkane moiety ( 5 ), which displays sub-nanomolar affinity and excellent D 3 R selectivity over the D 2 R. 25 Encouraged by these reports, we designed a new class of thiotriazole D 3 R selective scaffolds using commercially available diazaspiro alkanes A–H (Figure 2) as modified amino cores.…”

Section: Introductionmentioning

confidence: 99%

Highly Selective Dopamine D₃ Receptor Antagonists with Arylated Diazaspiro Alkane Cores

et al. 2017

View full text Add to dashboard Cite

A series of potent and selective D3 receptor (D3R) analogues with diazaspiro alkane cores were synthesized. Radioligand binding of compounds 11, 14, 15a, and 15c revealed favorable D3R affinity (Ki = 122–25.6 nM) and were highly selective for D3R vs D3R (ranging from 264–905-fold). Variation of these novel ligand architectures can be achieved using our previously reported 10–20 minute benchtop C–N cross-coupling methodology, affording a broad range of arylated diazaspiro pre-cursors.

show abstract

Recent advances in dopamine D₂ receptor ligands in the treatment of neuropsychiatric disorders

Jůza

Musílek

Mezeiová

et al. 2022

Medicinal Research Reviews

View full text Add to dashboard Cite

Dopamine is a biologically active amine synthesized in the central and peripheral nervous system. This biogenic monoamine acts by activating five types of dopamine receptors (D 1-5 Rs), which belong to the G protein-coupled receptor family. Antagonists and partial agonists of D 2 Rs are used to treat schizophrenia, Parkinson's disease, depression, and anxiety. The typical pharmacophore with high D 2 R affinity comprises four main areas, namely aromatic moiety, cyclic amine, central linker and aromatic/heteroaromatic lipophilic fragment. From the literature reviewed herein, we can conclude that 4-(2,3-dichlorophenyl), 4-(2-methoxyphenyl)-, 4-(benzo[b]thiophen-4-yl)-1-substituted piperazine, and 4-(6fluorobenzo[d]isoxazol-3-yl)piperidine moieties are critical for high D 2 R affinity. Four to six atoms chains are optimal for D 2 R affinity with 4-butoxyl as the most pronounced one. The bicyclic aromatic/heteroaromatic systems are most frequently occurring as lipophilic appendages to retain high D 2 R affinity. In this review, we provide a thorough overview of the therapeutic potential of D 2 R modulators in the treatment of the aforementioned disorders. In addition, this review summarizes current knowledge about these diseases, with a focus on the dopaminergic pathway underlying these pathologies. Major attention is paid to the structure, function, and pharmacology of novel D 2 R ligands, which have been developed in the last decade (2010-2021), and belong to the 1,4-disubstituted aromatic cyclic amine group. Due to the abundance of data,

show abstract

1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists

Cited by 18 publications

References 28 publications

Novel, Selective, and Developable Dopamine D₃ Antagonists with a Modified “Amino” Region

Novel, Selective, and Developable Dopamine D₃ Antagonists with a Modified “Amino” Region

Highly Selective Dopamine D₃ Receptor Antagonists with Arylated Diazaspiro Alkane Cores

Recent advances in dopamine D₂ receptor ligands in the treatment of neuropsychiatric disorders

Contact Info

Product

Resources

About

1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists

Cited by 18 publications

References 28 publications

Novel, Selective, and Developable Dopamine D3 Antagonists with a Modified “Amino” Region

Novel, Selective, and Developable Dopamine D3 Antagonists with a Modified “Amino” Region

Highly Selective Dopamine D3 Receptor Antagonists with Arylated Diazaspiro Alkane Cores

Recent advances in dopamine D2 receptor ligands in the treatment of neuropsychiatric disorders

Contact Info

Product

Resources

About

Novel, Selective, and Developable Dopamine D₃ Antagonists with a Modified “Amino” Region

Novel, Selective, and Developable Dopamine D₃ Antagonists with a Modified “Amino” Region

Highly Selective Dopamine D₃ Receptor Antagonists with Arylated Diazaspiro Alkane Cores

Recent advances in dopamine D₂ receptor ligands in the treatment of neuropsychiatric disorders