Conformationally Constrained Tricyclic HIV Integrase Inhibitors

Fardis, Maria; Jin, Haolun; Chen, Xiaowu; Tsiang, Manuel; Chen, James; Kim, Choung; Wright, Matthew

doi:10.1002/9781118015377.ch16

Cited by 3 publications

(3 citation statements)

References 38 publications

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“…As expected, conformational rigidity resulted in increased inhibitory potency toward HIV and IN, compared with that of 71 (Figure 20). 109 Compared with the N-methyl hydroxamate 75, the LLE value of the rigid rotamer N-hydroxydihydronaphthyridinone 76a was dramatically increased. 110 Another derivative 76b (PF-4776548) was disclosed as a promising candidate with high activity and a high barrier to resistance (Figure 20).…”

Section: Rationally Designed Multitarget-directed Ligands (Mtdls)mentioning

confidence: 96%

Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends

et al. 2015

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The early effectiveness of combinatorial antiretroviral therapy (cART) in the treatment of HIV infection has been compromised to some extent by rapid development of multidrug-resistant HIV strains, poor bioavailability, and cumulative toxicities, and so there is a need for alternative strategies of antiretroviral drug discovery and additional therapeutic agents with novel action modes or targets. From this perspective, we first review current strategies of antiretroviral drug discovery and optimization, with the aid of selected examples from the recent literature. We highlight the development of phosphate ester-based prodrugs as a means to improve the aqueous solubility of HIV inhibitors, and the introduction of the substrate envelope hypothesis as a new approach for overcoming HIV drug resistance. Finally, we discuss future directions for research, including opportunities for exploitation of novel antiretroviral targets, and the strategy of activation of latent HIV reservoirs as a means to eradicate the virus.

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Section: Rationally Designed Multitarget-directed Ligands (Mtdls)mentioning

confidence: 96%

Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends

et al. 2015

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“…And in consequence, compared with the potency of compound 33, impact of conformation rigidity on activity of inhibitors toward HIV and IN is obvious ( Figure 6) [40].…”

Section: -36mentioning

confidence: 98%

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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“…These efforts provide several distinct structural classes. Some second-generation drug targeting IN, such as dolutegravir (DTG, 2 ) [13], which has been approved for clinical use, and GSK364735 ( 3 ) [14,15] is in phase II clinical trials (Figure 1). Although they display superior characteristics to RAL and EVG, the cross-resistance has still been observed and the subsequent secondary mutations diminish the inhibitory activity [16,17,18].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anti-HIV-1 Activity Evaluation for Novel 3a,6a-Dihydro-1H-pyrrolo[3,4-c]pyrazole-4,6-dione Derivatives

et al. 2016

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Abstract:The search for new molecular constructs that resemble the critical two-metal binding pharmacophore and the halo-substituted phenyl functionality required for HIV-1 integrase (IN) inhibition represents a vibrant area of research within drug discovery. As reported herein, we have modified our recently disclosed 1-[2-(4-fluorophenyl)ethyl]-pyrrole-2,5-dione scaffolds to design 35 novel compounds with improved biological activities against HIV-1. These new compounds show single-digit micromolar antiviral potencies against HIV-1 and low toxicity. Among of them, compound 9g and 15i had potent anti-HIV-1 activities (EC 50 < 5 µM) and excellent therapeutic index (TI, CC 50 /EC 50 > 100). These two compounds have potential as lead compounds for further optimization into clinical anti-HIV-1 agents.

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Conformationally Constrained Tricyclic HIV Integrase Inhibitors

Cited by 3 publications

References 38 publications

Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends

Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends

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

Synthesis and Anti-HIV-1 Activity Evaluation for Novel 3a,6a-Dihydro-1H-pyrrolo[3,4-c]pyrazole-4,6-dione Derivatives

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