Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors

Peese, Kevin M.; Naidu, B. Narasimhulu; Patel, Manoj; Li, Chen; Langley, David R.; Terry, Brian; Protack, Tricia; Gali, Volodymyr; Lin, Zheng‐Zhe; Samanta, Himadri; Zheng, Ming; Jenkins, Susan; Dicker, Ira B.; Krystal, Mark; Meanwell, Nicholas A.; Walker, Michael

doi:10.1016/j.bmcl.2019.126784

Cited by 6 publications

(5 citation statements)

References 21 publications

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“…Very recently, a series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors were prepared and tested by Peese and co-workers at Bristol-Myers Squibb, USA . The purpose of this study was to search for a potent HIV-1 integrase inhibitor that can resolve the issues for the development of resistance mutations associated with the first generation integrase inhibitors raltegravir and elvitegravir.…”

Section: Five-membered Ring Heterocycles As Amide Bioisosteresmentioning

confidence: 99%

Section: Five-membered Ring Heterocycles As Amide Bioisosteresmentioning

confidence: 99%

“…Very recently, a series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors were prepared and tested by Peese and co-workers at Bristol-Myers Squibb, USA. 130 The purpose of this study was to search for a potent HIV-1 integrase inhibitor that can resolve the issues for the development of resistance mutations associated with the first generation integrase inhibitors raltegravir and elvitegravir. Recently, two new integrase strand transfer inhibitors (INSTI's), dolutegravir and bictegravir, gained FDA approval, and because of their reduced resistance mutation profile, they have been considered second generation integrase inhibitors.…”

Section: ■ Introductionmentioning

confidence: 99%

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Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

et al. 2020

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The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, pK a, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.

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Section: Five-membered Ring Heterocycles As Amide Bioisosteresmentioning

confidence: 99%

Section: Five-membered Ring Heterocycles As Amide Bioisosteresmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

et al. 2020

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“…A debenzylation and dechlorination of imidazole process yielded the imidazole based optimized INSTI (162) (Scheme 36). [86]…”

Section: Synthesis Of Pyrimidinone Instismentioning

confidence: 99%

Development of Synthetic Approaches Towards HIV Integrase Strand Transfer Inhibitors (INSTIs)

et al. 2022

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A clear and precise report on synthetic methods for INSTIs and their intermediates are provided in the present work. HIV Integrase strand transfer inhibitors (INSTIs), a class of antiretroviral agents employed to treat HIV infected patients are placed as the second option of treatment after nucleosides. As INSTIs are employed as first line therapy to newly infected HIV positive individuals, thus synthetic routes must be easily accessible to the medicinal chemists towards lead optimization or process development. The current perspective elaborates synthetic routes of first to next generation INSTIs investigated in two decades of research and their development efforts. Further, drug resistance occurred by mutations against usage of INSTI drugs with respect to their generation also discussed. Later, discussion about synthetic development and investigation of next generation INSTIs against drug resistance HIV infections also covers to fill the gap between first/second generation INSTIs. The current perspective will draw attention of medicinal chemists and multi‐disciplinary researchers in HIV drug discovery.

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“…Replacing it with a variety of bioisosteres provides a rewarding strategy in lead optimization as the amide bond often suffers from metabolic instability and results in physicochemical and pharmacokinetic complications such as poor solubility or permeability. , There are a number of reports exploiting 3-aminooxetane, fluoroalkene, − CF 3 -ethylamine, and sulfonamide among other functional groups to replace amide scaffolds in the medicinal chemistry literature (Figure ). Perhaps heterocycles represent the most appreciated and frequently employed amide bioisosteres. − Heterocyclic groups are highly diverse in terms of the ring size and heteroatom spatial distribution, with aromatic heterocycles most often exemplified. As a class of nonaromatic heterocycles, 5,5-disubstituted imidazol-4-ones appear several times in the medicinal chemistry and patent − literature and have been used to replace urea or peptide functionalities, yet have rarely been utilized in amide bond replacement.…”

Section: Introductionmentioning

confidence: 99%

Imidazolone as an Amide Bioisostere in the Development of β-1,3-N-Acetylglucosaminyltransferase 2 (B3GNT2) Inhibitors

Jackson,

Siegmund,

Bai

et al. 2023

J. Med. Chem.

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Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors

Cited by 6 publications

References 21 publications

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

Development of Synthetic Approaches Towards HIV Integrase Strand Transfer Inhibitors (INSTIs)

Imidazolone as an Amide Bioisostere in the Development of β-1,3-N-Acetylglucosaminyltransferase 2 (B3GNT2) Inhibitors

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