Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors: Use of a carboxylate prodrug to improve bioavailability

Ikuma, Yohei; Hochigai, Hitoshi; Kimura, Hidenori; Nunami, Noriko; Kobayashi, Tomonori; Uchiyama, Katsuya; Umezome, Takashi; Sakurai, Yasumitsu; Sawada, Naoyuki; Tadano, Jun; Sugaru, Eiji; Ono, Michiko; Hirose, Yuko; Nakahira, Hiroyuki

doi:10.1016/j.bmc.2014.12.051

Cited by 13 publications

(3 citation statements)

References 31 publications

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“…64 An ester prodrug of compound 64 improved oral absorption and in vivo efficacy. 128 producing a more sustained and consistent DPP-4 inhibition than trelagliptin in rats. 134 The cocrystal structures of compounds 58 and 68 were selected to illustrate the binding modes for the 2-cyanobenzylbased analogues of alogliptin.…”

Section: -Cyanobenzyl-basedmentioning

confidence: 89%

“…Introduction of a carboxylic acid into the benzo ring resulted in compound 63 with more potent DPP-4 activity ( IC 50 = 0.48 nM) and excellent selectivity over DPP-2 and DPP-8/9, but it suffered from low oral bioavailability . An ester prodrug of compound 64 improved oral absorption and in vivo efficacy . Shu et al from XuanZhu Pharma identified compound 65 (imigliptin, DPP-4 IC 50 = 9.0 nM) via a scaffold-hopping approach from alogliptin, which is a highly selective and oral active DPP-4 inhibitor entering into phase II clinical trials .…”

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: 89%

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

confidence: 99%

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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“…The extremely low bioavailability (<0.1%) of the dipeptidyl peptidase-IV (DPP-IV) inhibitor 2br in the rat was attributed to poor intrinsic membrane permeability that compromised absorption and was believed to be a function of the zwitterionic nature of the molecule, which incorporates both primary amine and carboxylic acid functionalities (Table 7). 138 The simple methyl ester 2bs functioned as a prodrug, with a high rate of metabolism in rat liver S9 and moderate serum stability but exhibited disappointing oral bioavailability ( F = 2.4%), despite its improved permeability in a PAMPA (parallel membrane permeability artificial) assay compared to the parent drug. The pivaloyloxymethyl ester prodrug 2bt , which was subject to rapid metabolism in human liver S9, exhibited insufficient conversion to the parent drug in human serum.…”

Section: Design Of Prodrugs To Improve Oral Absorption and Bioavailab...mentioning

confidence: 99%

Prodrugs as empowering tools in drug discovery and development: recent strategic applications of drug delivery solutions to mitigate challenges associated with lead compounds and drug candidates

Subbaiah,

Rautio,

Meanwell

2024

Chem. Soc. Rev.

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New tetrazoloquinolinyl methoxyphenyl-4-thiazolidinones: synthesis and antihyperglycemic evaluation

et al. 2016

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Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors: Use of a carboxylate prodrug to improve bioavailability

Cited by 13 publications

References 31 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

Prodrugs as empowering tools in drug discovery and development: recent strategic applications of drug delivery solutions to mitigate challenges associated with lead compounds and drug candidates

New tetrazoloquinolinyl methoxyphenyl-4-thiazolidinones: synthesis and antihyperglycemic evaluation

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