Design, synthesis and evaluation of a series of novel long-acting dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes

Lin, Cheng Huang; Kong, Ying; Wang, Furong; Rong, Rong; Li, Xiangping; Xiao, Rensong; Wu, Ziqi; Zhang, Qiuyan; Wang, Lin

doi:10.1016/j.bioorg.2022.105767

Cited by 2 publications

(4 citation statements)

References 33 publications

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“…157 Recently, Lin et al discovered compound 102 as a long-acting DPP-4 inhibitor by introducing heterocycles into the pyrazole ring of omarigliptin to improve its lipophilicity. 158 Compound 102 exhibited a half-life of 25.4 h, which was significantly longer than that of omarigliptin in rats. A oncebiweekly dose of compound 102 showed better hypoglycemic efficacy than omarigliptin in male HFD/STZ-induced diabetes C57BL/6 mice.…”

Section: -Cyanobenzyl-basedmentioning

confidence: 94%

“…A oncebiweekly dose of compound 102 showed better hypoglycemic efficacy than omarigliptin in male HFD/STZ-induced diabetes C57BL/6 mice. 158 The X-ray crystal structure of fluoroomarigliptin is shown in Figure 25A. Fluoroomarigliptin shows a similar binding mode and shares the same key interactions in the DPP-4 active site as sitagliptin and other above-mentioned ring-constrained DPP-4 inhibitors.…”

Section: -Cyanobenzyl-basedmentioning

confidence: 99%

“…The author proposed that the prolonged duration of ZY15557 was due to a combination of the long plasma half-life and slow dissociation of ZY15557 bound to DPP-4 . Recently, Lin et al discovered compound 102 as a long-acting DPP-4 inhibitor by introducing heterocycles into the pyrazole ring of omarigliptin to improve its lipophilicity . Compound 102 exhibited a half-life of 25.4 h, which was significantly longer than that of omarigliptin in rats.…”

Section: Structural Evolution From Lead Compounds To Long-acting Dpp-...mentioning

confidence: 99%

“…Compound 102 exhibited a half-life of 25.4 h, which was significantly longer than that of omarigliptin in rats. A once-biweekly dose of compound 102 showed better hypoglycemic efficacy than omarigliptin in male HFD/STZ-induced diabetes C57BL/6 mice …”

Section: Structural Evolution From Lead Compounds To Long-acting Dpp-...mentioning

confidence: 99%

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Development of Long-Acting Dipeptidyl Peptidase-4 Inhibitors: Structural Evolution and Long-Acting Determinants

Li,

Deng,

et al. 2023

J. Med. Chem.

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Considerable effort has been made to achieve less frequent dosing in the development of DPP-4 inhibitors. Enthusiasm for long-acting DPP-4 inhibitors is based on the promise that such agents with less frequent dosing regimens are associated with improved patient adherence, but the rational design of long-acting DPP-4 inhibitors remains a major challenge. In this Perspective, the development of longacting DPP-4 inhibitors is comprehensively summarized to highlight the evolution of initial lead compounds on the path toward developing long-acting DPP-4 inhibitors over nearly three decades. The determinants for long duration of action are then examined, including the nature of the target, potency, binding kinetics, crystal structures, selectivity, and preclinical and clinical pharmacokinetic and pharmacodynamic profiles. More importantly, several possible approaches for the rational design of long-acting drugs are discussed. We hope that this information will facilitate the design and development of safer and more effective long-acting DPP-4 inhibitors and other oral drugs. ■ SIGNIFICANCE• The evolution of initial lead compounds on the path toward developing long-acting DPP-4 inhibitors over nearly three decades is reviewed. • The determinants for long duration of action are examined, including the nature of the target, potency, binding kinetics, crystal structures, selectivity, and preclinical and clinical PK and PD profiles. • Possible approaches for the rational design of longacting drugs are discussed.

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Section: -Cyanobenzyl-basedmentioning

confidence: 94%

Section: -Cyanobenzyl-basedmentioning

confidence: 99%

Section: Structural Evolution From Lead Compounds To Long-acting Dpp-...mentioning

confidence: 99%

Section: Structural Evolution From Lead Compounds To Long-acting Dpp-...mentioning

confidence: 99%

See 2 more Smart Citations

Development of Long-Acting Dipeptidyl Peptidase-4 Inhibitors: Structural Evolution and Long-Acting Determinants

Li,

Deng,

et al. 2023

J. Med. Chem.

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Root-Extracted lignanamides from Limonium gmelinii (Willd.) Kuntze with a potential PTP1B inhibitory activity by regulating PI3K/AKT signaling pathway

Tuohongerbieke

Liu

et al. 2023

Bioorganic Chemistry

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Design, synthesis and evaluation of a series of novel long-acting dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes

Cited by 2 publications

References 33 publications

Development of Long-Acting Dipeptidyl Peptidase-4 Inhibitors: Structural Evolution and Long-Acting Determinants

Development of Long-Acting Dipeptidyl Peptidase-4 Inhibitors: Structural Evolution and Long-Acting Determinants

Root-Extracted lignanamides from Limonium gmelinii (Willd.) Kuntze with a potential PTP1B inhibitory activity by regulating PI3K/AKT signaling pathway

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