Synthesis, SAR and evaluation of [1,4′]-bipiperidinyl-4-yl-imidazolidin-2-one derivatives as novel CCR5 antagonists

Rotstein, David M.; Gabriel, Stephen D.; Manser, Nicole; Filonova, L. K.; Padilla, Fernando; Sankuratri, Surya; Ji, Changhua; deRosier, André; Dioszegi, Marianna; Heilek, Gabrielle; Jekle, Andreas; Weller, Paul; Berry, Pamela

doi:10.1016/j.bmcl.2010.04.077

Cited by 11 publications

(11 citation statements)

References 7 publications

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“…In the development of a small-molecule CCR5 antagonist, the conformational constrain-based design was adopted with aim to fix the basic motif into a desired orientation for effective binding with CCR5. These effects afforded novel CCR5 antagonists, such as imidazolone 23 [34], 24 [35], 26, 27 [36], and 1,3,4-trisubstituted pyrrolidine 29 [37], which have the potential to be promising candidates for future development. It's worth mentioning that, to some extent, the discovery of approved drug maraviroc (31) was also benefited from contributions of the conformational constrain approach (Figure 3) [38].…”

Section: Chemokine (C-x-c Motif) Receptor Type 4 Antagonistsmentioning

confidence: 99%

Conformational Restriction: An Effective Tactic in ‘Follow-On’-Based Drug Discovery

et al. 2014

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The conformational restriction (rigidification) of a flexible ligand has often been a commonly used strategy in drug design, as it can minimize the entropic loss associated with the ligand adopting a preferred conformation for binding, which leads to enhanced potency for a given physiological target, improved selectivity for isoforms and reduced the possibility of drug metabolism. Therefore, the application of conformational restriction strategy is a core aspect of drug discovery and development that is widely practiced by medicinal chemists either deliberately or subliminally. The present review will highlight current representative examples and a brief overview on the rational design of conformationally restricted agents as well as discuss its advantages over the flexible counterparts.

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Section: Chemokine (C-x-c Motif) Receptor Type 4 Antagonistsmentioning

confidence: 99%

Conformational Restriction: An Effective Tactic in ‘Follow-On’-Based Drug Discovery

et al. 2014

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“…[64] Rotstein et al replaced the spiro group with an imidazolidinone ring (bioisostere) to obtain compound 18 and its derivatives. [64] Rotstein et al replaced the spiro group with an imidazolidinone ring (bioisostere) to obtain compound 18 and its derivatives.…”

Section: Imidazolidinones As Ccr5 Antagonistsmentioning

confidence: 99%

“…Researchers at Roche found that compound 17,containing a spiro ring, is agood CCR5 antagonist. [64] Rotstein et al replaced the spiro group with an imidazolidinone ring (bioisostere) to obtain compound 18 and its derivatives. [64] They found that the CCR5 receptor bindingp ocket is lipophilic in nature, and compounds with high lipophilicity exhibit good potency.H ow- [a] EC 50 values in the presence of 0% human serum( HS).…”

Section: Imidazolidinones As Ccr5 Antagonistsmentioning

confidence: 99%

“…[64] Rotstein et al replaced the spiro group with an imidazolidinone ring (bioisostere) to obtain compound 18 and its derivatives. [64] They found that the CCR5 receptor bindingp ocket is lipophilic in nature, and compounds with high lipophilicity exhibit good potency.H ow- [a] EC 50 values in the presence of 0% human serum( HS). ChemMedChem 2019, 14,291 -302 www.chemmedchem.org ever,h ighly lipophilicc ompounds have low metabolic stability and high clearance issues.T hey therefore tried to design a scaffold with balanced antiviral activity and higher metabolic stability.…”

Section: Imidazolidinones As Ccr5 Antagonistsmentioning

confidence: 99%

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Imidazolidinones and Imidazolidine‐2,4‐diones as Antiviral Agents

Swain

Mohanty

2019

ChemMedChem

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Imidazolidinones and imidazolidine‐2,4‐diones are important classes of heterocyclic compounds that possess potent activities against several viruses such as dengue virus, enterovirus, hepatitis C virus (HCV), and human immunodeficiency virus (HIV). The first imidazolidinone derivative as an anti‐HIV agent was reported in 1996. Imidazolidinones inhibit HIV aspartic protease activity, and also act as CCR5 co‐receptor antagonists. Significant effort has been devoted to the design of various imidazolidinone analogues that are active against drug‐resistant HIV strains, with fewer side effects. Different scaffolds have been designed through both rational drug design strategies and computer‐aided drug design. Imidazolidinones have been found to be potent against HIV, and preclinical studies are currently in progress. There are some reports of imidazolidinones as having both anti‐HCV and anti‐dengue virus activity, and more research has yet to be done along these lines. These compounds inhibit NS3 serine protease of HCV, and NS2B‐NS3 protease of dengue virus. Pyridyl‐imidazolidinones possess very specific and potent activity against human enterovirus 71 (EV71) by targeting the EV71 capsid protein VP1, and inhibiting viral adsorption and/or viral RNA uncoating.

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“…Imidazolidinone rings ( 1 ) are found in a wide array of useful organic compounds including chiral auxiliaries , antifungals , BACE‐1 inhibitors , 5‐HT 2C , NMDA and CCR5 receptor antagonists, and androgen receptor modulators . One of the more direct routes to these compounds involves cyclization of N ‐(2‐hydroxyethyl)ureas (eq.…”

Section: Introductionmentioning

confidence: 99%

Alkali Carbonate Effects onN-(2-Hydroxyethyl)ureaCyclization: Application to a 2-Imidazolidinone Scale-Up

Káldor

Spitzer

Duan

et al. 2013

J. Heterocyclic Chem.

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Synthesis, SAR and evaluation of [1,4′]-bipiperidinyl-4-yl-imidazolidin-2-one derivatives as novel CCR5 antagonists

Cited by 11 publications

References 7 publications

Conformational Restriction: An Effective Tactic in ‘Follow-On’-Based Drug Discovery

Conformational Restriction: An Effective Tactic in ‘Follow-On’-Based Drug Discovery

Imidazolidinones and Imidazolidine‐2,4‐diones as Antiviral Agents

Alkali Carbonate Effects onN-(2-Hydroxyethyl)ureaCyclization: Application to a 2-Imidazolidinone Scale-Up

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