Triazolyl Azabicyclo[3.1.0]hexanes: a Class of Potent and Selective Dopamine D<sub>3</sub> Receptor Antagonists

Bonanomi, Giorgio; Braggio, Simone; Capelli, Anna Maria; Checchia, Anna; Fabio, Romano Di; Marchioro, Carla; Tarsi, Luca; Tedesco, Giovanna; Terreni, Silvia; Worby, Angela; Heibreder, Christian; Micheli, Fabrizio

doi:10.1002/cmdc.201000026

Cited by 17 publications

(19 citation statements)

References 21 publications

(35 reference statements)

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“…Inspired by a recent study investigating similar characteristics of a series of triazole-based dopamine D 3 receptor antagonists, [7] point charges (in the form of atom partial charges) Figure 3. Electrostatic potential (ESP) surfaces of five compounds containing an unsubstituted 5-membered ring at the crucial R 1 position; these derivatives have varying antiprion potency.…”

Section: Computational Analysis Of Factors Influencing Activitymentioning

confidence: 99%

Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease

et al. 2010

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Structure-activity relationships within the indole-3-glyoxylamide series of antiprion agents have been explored further, resulting in discovery of several new compounds demonstrating excellent activity in a cell line model of prion disease (EC₅₀ <10 nM). After examining a range of substituents at the para-position of the N-phenylglyoxylamide moiety, five-membered heterocycles containing at least two heteroatoms were found to be optimal for the antiprion effect. A number of modifications were made to probe the importance of the glyoxylamide substructure, although none were well tolerated. The most potent compounds did, however, prove largely stable towards microsomal metabolism, and the most active library member cured scrapie-infected cells indefinitely on administration of a single treatment. The present results thereby confirm the indole-3-glyoxylamides as a promising lead series for continuing in vitro and in vivo evaluation against prion disease.

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Section: Computational Analysis Of Factors Influencing Activitymentioning

confidence: 99%

Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease

et al. 2010

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“…In addition, as the template is long to begin with, and addition of molecular “decoration” has added MW and lipophilicity, confounding activity at hERG channels, for example, has precluded further development of otherwise selective and promising agents due to predicted cardiotoxicity. Significant effort has been made in recent years (Bonanomi et al, 2010; Butini et al, 2010; Micheli et al, 2007; Micheli & Heidbreder, 2013) to address this persistent challenge with this class of drugs.…”

Section: D3-selective Drug Design Using Small Molecule Sarmentioning

confidence: 99%

“…Although an extended aryl amide was thought to be required for high-affinity binding at D3, and also for selectivity over D2 and 5-HT 1A , there are several recent examples - especially with the triazole analogs - in which much smaller aryl ring systems provided comparable D3 selectivity and affinity profiles with reduced lipophilicity and molecular weights, which is more favorable for successful drug development (Bonanomi et al, 2010; Micheli et al, 2010a; Micheli et al, 2010b; and others highlighted in Micheli & Heidbreder, 2013). The sulfoxide moiety was also used in other analogues reported in the patent literature to be D3-selective (Micheli & Heidbreder, 2013).…”

Section: D3-selective Drug Design Using Small Molecule Sarmentioning

confidence: 99%

“…Other groups have compared homology models for the D3 receptor with homology models for the hERG channel in an attempt to optimize their molecules for high-affinity binding to the D3 receptor while reducing affinity for the hERG channel (Bonanomi et al, 2010; Micheli et al, 2010b; Micheli et al, 2007). This effort has resulted in the discovery of D3-selective antagonists without predicted QT interval prolongation, a very important finding for drug development.…”

Section: D3-selective Drug Design Using Small Molecule Sarmentioning

confidence: 99%

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Beyond Small-Molecule SAR

Keck

Burzynski

Shi

et al. 2014

Advances in Pharmacology

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The dopamine D3 receptor is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, restless leg syndrome, and drug addiction. The high protein sequence homology between the D3 and D2 receptors has posed a challenge to developing D3 receptor-selective ligands whose behavioral actions can be attributed to D3 receptor engagement, in vivo. However, through primarily small molecule structure-activity relationship (SAR) studies, a variety of chemical scaffolds have been discovered over the past two decades that have resulted in several D3 receptor-selective ligands with high affinity and in vivo activity. Nevertheless, viable clinical candidates remain limited. The recent determination of the high-resolution crystal structure of the D3 receptor has invigorated structure-based drug design, providing refinements to the molecular dynamic models and testable predictions about receptor-ligand interactions. This review will highlight recent preclinical and clinical studies demonstrating potential utility of D3 receptor-selective ligands in the treatment of addiction. In addition, new structure-based rational drug design strategies for D3 receptor-selective ligands that complement traditional small molecule SAR to improve the selectivity and directed efficacy profiles are examined.

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“…The theoretical calculation predicted that the reaction of disubstituted hydrazide 76 with compound 77 could smoothly occur, the experimental result showed that triazole 78 was successfully obtained in the presence of potassium carbonate as anticipated, and could be further transformed in THF at room temperature into azabicyclo[3.1.0]hexyl triazole derivative as potent antagonist of dopamine D3 receptor (Scheme 29) [110].…”

Section: Alkyl Hydrazidesmentioning

confidence: 99%

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

Zhang¹,

Damu²,

Cai³

et al. 2014

COC

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Heterocyclic 1,2,4-triazole derivatives possess unusually spacious potentiality as medicinal agents, agricultural chemicals, functional materials, ionic liquids, supramolecular catalysts as well as artificial enzymes and receptors for supramolecular recognition and biomimetic catalysis, and their various researches and developments have been being a quite rapidly developing and active highlight topic with an infinite space. Numerous efforts have been directed toward various types of possible applications of 1,2,4-triazole-based compounds and a lot of important progress has been made, especially their preparations have attracted increasing attention. This review systematically summarized the recent advances in the syntheses of 1,2,4-triazole derivatives, including: (1) Cyclizations to form triazole ring; (2) Transformations of heterocyclic compounds to construct triazole ring; (3) Substitutions on 1,2,4-triazole ring; (4) Structural modifications in side chains of 1,2,4-triazole ring. It was hoped that this review would be helpful for the design and development of highly efficient preparation of 1,2,4-triazole derivatives with various sorts and varieties of extensively potential applications in medicine, agriculture, chemistry, materials, supramolecular sciences and so on.

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Triazolyl Azabicyclo[3.1.0]hexanes: a Class of Potent and Selective Dopamine D₃ Receptor Antagonists

Cited by 17 publications

References 21 publications

Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease

Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease

Beyond Small-Molecule SAR

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

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Triazolyl Azabicyclo[3.1.0]hexanes: a Class of Potent and Selective Dopamine D3 Receptor Antagonists

Cited by 17 publications

References 21 publications

Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease

Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease

Beyond Small-Molecule SAR

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

Contact Info

Product

Resources

About

Triazolyl Azabicyclo[3.1.0]hexanes: a Class of Potent and Selective Dopamine D₃ Receptor Antagonists