Structural development of 1H-pyrazolo-[3,4-b]pyridine-4-carboxylic acid derivatives as human peroxisome proliferator-activated receptor alpha (PPARα)-selective agonists

Miyachi, Hiroyuki; Yuzuriha, Tomohiro; Tabata, Ryotaro; Fukuda, Syohei; Nunomura, Kazuto; Lin, Bangzhong; Kobayashi, Toshimichi; Ishimoto, Kenji; Doi, Takefumi; Tachibana, Keisuke

doi:10.1016/j.bmcl.2019.06.062

Cited by 10 publications

(8 citation statements)

References 13 publications

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“…These results indicate that shape complementarity in this cavity is essential for the activity of 1H-pyrazolo-[3,4-b]pyridine derivatives. The SAR study, in which substitution at this position with an m-halophenyl ring was not allowed 20 , supports the importance of the steric contribution at this site.…”

Section: Structural Basis Of Agonism Of 1h-pyrazolo-[34-b]pyridine Dmentioning

confidence: 57%

“…Chemicals. Compounds A and B were synthesized as reported previously 20 . All other chemicals were obtained from Nacalai Tesque (Kyoto, Japan) unless otherwise indicated.…”

Section: Methodsmentioning

confidence: 99%

“…2), these hydrophobic groups in this site may contribute to stabilizing the active conformation of H12. Indeed, it has been shown that smaller substituents such as a methyl or cyclopropyl group at this position decreased the activity 20 . In the previously reported structure of PPARα-LBD complexed with BMS-631707 (PDB ID: 2REW), a methoxy benzene ring was buried in the cavity.…”

Section: Structural Basis Of Agonism Of 1h-pyrazolo-[34-b]pyridine Dmentioning

confidence: 99%

“…Thus, 1H-pyrazolo- [3,4-b]pyridine derivatives could be promising lead compounds for dyslipidemia owing to their low associated risk 17 . Most recently, it was shown that the structure-activity-relationships (SAR) of 1H-pyrazolo-[3,4-b]pyridine derivatives were somewhat different from those of fibrates 20 . However, the binding mode and structural basis of activity of 1H-pyrazolo-[3,4-b]pyridine derivatives, which are important for improving their efficacy, remains unknown.…”

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confidence: 99%

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Structural Basis for PPARα Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives

Yoshida

Oki

Doi

et al. 2020

Sci Rep

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Small-molecule agonism of peroxisome proliferator-activated receptor α (ppARα), a ligand-activated transcriptional factor involved in regulating fatty acid metabolism, is an important approach for treating dyslipidemia. Here, we determined the structures of the ligand-binding domain (LBD) of ppARα in complex with 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives, which were recently identified as PPARα-selective activators with markedly different structures from those of the wellknown ppARα agonists fibrates. The crystal structures of the complexes showed that they form a canonical hydrogen-bond network involving helix 12 in the LBD, which is thought to be essential for ppARα activation, as also observed for fibrates. However, the phenyl side chain of the compounds occupies a small cavity between Ile272 and Ile354, which is rarely accessed by fibrates. This unique feature may be essential for subtype selectivity and combine with the well-characterized binding mode of fibrates to improve activity. These findings demonstrate the advantage of using 1H-pyrazolo-[3,4-b] pyridine as a skeleton of PPARα agonists and provide insight into the design of molecules for treating dyslipidemia.

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Section: Structural Basis Of Agonism Of 1h-pyrazolo-[34-b]pyridine Dmentioning

confidence: 57%

“…Chemicals. Compounds A and B were synthesized as reported previously 20 . All other chemicals were obtained from Nacalai Tesque (Kyoto, Japan) unless otherwise indicated.…”

Section: Methodsmentioning

confidence: 99%

Section: Structural Basis Of Agonism Of 1h-pyrazolo-[34-b]pyridine Dmentioning

confidence: 99%

mentioning

confidence: 99%

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Structural Basis for PPARα Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives

Yoshida

Oki

Doi

et al. 2020

Sci Rep

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“…Among the N ‐heterocycles, the fused pyrazolo‐pyridine derivatives have received considerable attention because of their broad‐spectrum of biological profiles and thus constitute a versatile synthetic building block in drug discovery. Many of these possess various pharmacological activities including FGFR kinase inhibition, [16] antiproliferative, [17] antimicrobial and anticancer, [18] hPPAR α agonist [19] and human A1 adenosine antagonist activities [20] . Therefore, the preparation of pyrazolo[3,4‐ b ]pyridine scaffolds is highly desirable for their immense biological applications.…”

Section: Introductionmentioning

confidence: 99%

Polyethylene glycol (PEG‐400) Mediated One‐pot Green Synthesis of 4,7‐Dihydro‐2H‐pyrazolo[3,4‐b]pyridines Under Catalyst‐free Conditions

et al. 2020

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Polyethylene glycol (PEG‐400) was proved a highly efficient and green solvent reaction medium for the synthesis of series of novel 3,6‐dimethyl‐4,7‐dihydro‐2H‐pyrazolo[3,4‐b]pyridine derivatives with excellent yields by a three‐component reaction of 1H‐pyrazol‐3‐amino‐5‐methyl, various aromatic or heteroaromatic aldehydes and chosen CH‐active compounds under catalyst‐free conditions via one‐pot strategy. This transformation is compatible with a broad diversity of functional group tolerance. Rapid synthesis, mild reaction conditions, high yields, no catalyst or column chromatography, cost‐effectiveness and green solvent are the benefits of this protocol.

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Methods for the synthesis of 1H-pyrazolo[3,4-b]pyridine derivatives

et al. 2022

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Structural development of 1H-pyrazolo-[3,4-b]pyridine-4-carboxylic acid derivatives as human peroxisome proliferator-activated receptor alpha (PPARα)-selective agonists

Cited by 10 publications

References 13 publications

Structural Basis for PPARα Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives

Structural Basis for PPARα Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives

Polyethylene glycol (PEG‐400) Mediated One‐pot Green Synthesis of 4,7‐Dihydro‐2H‐pyrazolo[3,4‐b]pyridines Under Catalyst‐free Conditions

Methods for the synthesis of 1H-pyrazolo[3,4-b]pyridine derivatives

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