Discovery and biological evaluation of novel pyrazolopyridine derivatives as potent and orally available PI3Kδ inhibitors

Hamajima, Toshihiro; Takahashi, Fumie; Katô, Kôji; Mukoyoshi, Koichiro; Yoshihara, Kousei; Yamaki, Shohei; Sugano, Yukihito; Moritomo, Ayako; Yamagami, Kaoru; Yokoo, Koji; Fukahori, Hidehiko

doi:10.1016/j.bmc.2018.03.042

Cited by 15 publications

(9 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1 H NMR (400 MHz, DMSO- d 6 ): δ 12.24 (1H, s, NH), 10.82 (1H, s, NH), 10.5 (1H, s, NH), 8.42 (1H, d, J = 7.6 Hz, 10–H), 7.66 (1H, dt, J = 7.8 and 1.2 Hz), 7.43 (1H, t, J = 7.2 Hz), 7.38 (1H, dd, J = 8.4 and 0.8 Hz), 7.15 (1H, dt, J = 7.6 and 1.2 Hz), 6.93–6.84 (3H, m), 1.64 (3H, s, CH 3 ). 13 C NMR (100 MHz, DMSO- d 6 ): δ 8.6 (CH 3 ), 48.9 (C spiro ), 94.8, 100.1, 108.8, 113.6, 116.7, 121.7, 123.2, 123.3, 124.0, 127.6, 132.2, 134.6, 136.5, 141.6, 145.6, 146.1, 152.0, 159.5 (CO), 179.0 (CO). MS (EI, 70 eV): m / z = 370 (M + , 5), 368 (M–2, 11), 246 (6), 236 (10), 152 (7), 123 (13), 111 (14), 97 (40), 83 (55), 69 (76), 57 (96), 43 (100).…”

Section: Methodsmentioning

confidence: 99%

“…Pyrazolopyridine is a privileged heterocyclic core existing in many synthetic compounds exhibiting inhibition of enterovirus replication 11 and angiogenesis, 12 and shows potential for the treatment of autoimmune diseases and leukocyte malignancies via PI3K inhibition. 13 Pyrazolopyridine-based compounds have also shown antileishmanial, 14 antimicrobial, antiquorum-sensing, and antitumor activities. 15 On the other hand, pyridocoumarin is the common scaffold of many compounds exhibiting a broad spectrum of diverse pharmaceutical properties, including antitumor, antimalarial, antiviral, central nervous system (CNS) depressant, antimicrobial, and anti-inflammatory activities.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A derivatization-directed three-component synthesis of fluorescent spiro [dihydropyridine-4,3ʹ-indoline]s

Najafizadeh

Rad‐Moghadam

Kalurazi

2020

Journal of Chemical Research

View full text Add to dashboard Cite

The synthesis of spiro[chromeno[4,3- b]pyrazolo[4,3- e]pyridine-7,3ʹ-indoline]s is achieved via three-component reactions of 5-amino-3-methylpyrazole, 4-aminocoumarin, and isatin derivatives. This protocol provides expedient synthesis of 10-unsubstituted derivatives of the parent heterocyclic spiro framework and does not lead to coumarin ring opening. The synthesis is highly convergent as no by-products are present in the reaction mixtures. The spiro products show violet fluorescence emissions depending on the nature of their substituents.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A derivatization-directed three-component synthesis of fluorescent spiro [dihydropyridine-4,3ʹ-indoline]s

Najafizadeh

Rad‐Moghadam

Kalurazi

2020

Journal of Chemical Research

View full text Add to dashboard Cite

show abstract

“…Schwehm et al [114] have reported the design of a novel tricyclic scaffold ( 35 ) which can be used as a tryptophan shelf binding motif (Figure 6c). Clinical candidates GSK2269557 ( 36 ) and GSK2292767 ( 37 ) both use the tryptophan shelf (PDB ID 5AE8, 5AE9) (Figure 6c) [73], as do a series of pyrazolopyridines described by Hamajima et al ( 38 , Figure 6c) [115].…”

Section: Structural Determinants Of Isoform Selectivitymentioning

confidence: 99%

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

Miller

Thompson²,

Gabelli

2019

Biomolecules

View full text Add to dashboard Cite

Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3K, PI3K, PI3K and PI3K have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity-activity relationship data to highlight key insights into how the various regions of the PI3K binding site influence isoform selectivity. The picture that emerges is one that is far from simple and emphasizes the complex nature of protein-inhibitor binding, involving protein flexibility, energetics, water networks and interactions with non-conserved residues.

show abstract

“…143 Surprisingly, until very recently there had not been any reports where others have attempted to take advantage of this motif; however in 2018 Astellas described a series with a pyrazolopyridine hinge binder that also exhibited good isoform selectivity (78). 144 ■ PYRIMIDINE/QUINOXALINE HINGE-BINDERS Novartis described the conversion of a nonselective PI3K and mTOR inhibitor (79) to a PI3Kδ inhibitor (80); 145 compounds were unusual in that the hinge-binding motif contained only an aromatic nitrogen as hydrogen bond acceptor and no donor. This series was modified by side chain simplification to improve physicochemical properties (81).…”

Section: ■ Selectivity Of Propeller Inhibitorsmentioning

confidence: 99%

“…Surprisingly, until very recently there had not been any reports where others have attempted to take advantage of this motif; however in 2018 Astellas described a series with a pyrazolopyridine hinge binder that also exhibited good isoform selectivity ( 78 ) …”

Section: “Nonpropeller” Shaped Inhibitors Indazole Hinge-bindersmentioning

confidence: 99%

Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases

et al. 2018

View full text Add to dashboard Cite

Phosphoinositol 3-kinases (PI3Ks) γ and δ are key enzymes in hematopoietic cells and have been seen as high-value targets for the treatment of diseases with inflammatory and immunomodulatory components since their discovery and the identification of their roles. In this Perspective we review progress in the application of inhibitors of PI3Kγ and δ to inflammatory and immunological conditions over the past 6 years. We consider progress in the understanding of the roles of PI3Kγ and PI3Kδ in immunology and inflammation, the experience from clinical trials where inhibitors have been tested, and what has been learned about the safety of their use. The extensive medicinal chemistry efforts to discover both isoform selective and dual PI3Kγδ inhibitors are analyzed and detailed. Developments in understanding the structural chemistry of the PI3K enzymes and the factors that govern isoform selectivity are discussed. The effects observed with the known inhibitor compounds in animal models are described.

show abstract

Discovery and biological evaluation of novel pyrazolopyridine derivatives as potent and orally available PI3Kδ inhibitors

Cited by 15 publications

References 25 publications

A derivatization-directed three-component synthesis of fluorescent spiro [dihydropyridine-4,3ʹ-indoline]s

A derivatization-directed three-component synthesis of fluorescent spiro [dihydropyridine-4,3ʹ-indoline]s

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases

Contact Info

Product

Resources

About