Discovery of novel BTK inhibitors with carboxylic acids

Gao, Xiaolei; Wang, James; Liu, Jian; Guiadeen, Deodial; Krikorian, A. D.; Boga, Sobhana Babu; Alhassan, Abdul-Basit; Selyutin, Oleg; Yu, Wei; Yu, Younong; Anand, Rajan; Liu, Shilan; Yang, Chundao; Wu, Hao; Cai, Jiaqiang; Cooper, Alan; Zhu, Haiyuan; Maloney, Kevin M.; Gao, Ying‐Duo; Fischmann, Thierry O.; Presland, Jeremy; Mansueto, My Sam; Xu, Zangwei; Leccese, Erica; Zhang-Hoover, Jie; Knemeyer, Ian; Garlisi, Charles G.; Bays, Nathan; Stivers, Peter; Brandish, Philip E.; Hicks, Alexandra; Kim, Ronald; Kozlowski, Joeseph A.

doi:10.1016/j.bmcl.2016.11.079

Cited by 18 publications

(9 citation statements)

References 14 publications

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“…However, analogues were shown to inhibit adenosine uptake (AdU) causing undesirable CV effects . To avoid these adverse effects optimization of the drug 310 was carried out by substituting the cyclohexane ring for cubane, BCO, and BCP . The cubane 311 and BCP 313 analogues showed reduced human whole blood (hWB) potency, whereas the BCO 312 analogue exhibited excellent potencies at the desired receptors but was poorly selective for AdU.…”

Section: Application Of Rigid‐linear Linkers In Small Molecule Drugsmentioning

confidence: 99%

“…[380] To avoid thesea dverse effects optimizationo ft he drug 310 was carriedo ut by substituting the cyclohexane ring for cubane, BCO, and BCP. [381] The cubane 311 and BCP 313 analogues showed reduced human whole blood (hWB) potency,w hereas the BCO 312 analoguee xhibited excellent potencies at the desired receptors but was poorly selective for AdU. The addition of an ethoxy group onto the centralb enzene ring of the compound 312 b resulted in the retention of good potencyw hile reducing adenosine uptake activity.B ut unfortunately,ahigh metabolic clearance was observed for this compound making further optimizationn ecessary before it can be effective.…”

Section: Aliphatic Bioisosteresmentioning

confidence: 99%

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Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry

Locke

Bernhard

Senge

2019

Chemistry A European J

197

143

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Nonconjugated hydrocarbons, like bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, triptycene, and cubane are a unique class of rigid linkers. Due to their similarity in size and shape they are useful mimics of classic benzene moieties in drugs, so‐called bioisosteres. Moreover, they also fulfill an important role in material sciences as linear linkers, in order to arrange various functionalities in a defined spatial manner. In this Review article, recent developments and usages of these special, rectilinear systems are discussed. Furthermore, we focus on covalently linked, nonconjugated linear arrangements and discuss the physical and chemical properties and differences of individual linkers, as well as their application in material and medicinal sciences.

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Section: Application Of Rigid‐linear Linkers In Small Molecule Drugsmentioning

confidence: 99%

Section: Aliphatic Bioisosteresmentioning

confidence: 99%

Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry

Locke

Bernhard

Senge

2019

Chemistry A European J

197

143

View full text Add to dashboard Cite

show abstract

“…Various polycyclic linkers were also explored as inhibitors of Bruton's tyrosine kinase, namely, compounds 80. 93 In all cases, IC 50 values between 0.1 and 0.4 nM were found, indicating great tolerance for this alteration. Potencies translated to human peripheral blood mononuclear cell and human whole blood activity studies.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 82%

Cubanes in Medicinal Chemistry

2018

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Cubane is a highly strained saturated hydrocarbon system that has historically been of interest in theoretical organic chemistry. More recently it has become a molecule of interest for biological applications due to its inherent stability and limited toxicity. Of greater significance is the ability to potentially functionalize cubane at each of its carbon atoms, providing complex biologically active molecules with unique spatial arrangements for probing active sites. These characteristics have led to an increased use of cubane in pharmaceutically relevant molecules. In this Perspective we describe synthetic methodology for accessing a range of functionalized cubanes and their applications in pharmaceuticals. We also provide some perspectives on challenges and future directions in the advancement of this field.

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“…Later, to further optimize potency, selectivity parameters, PK parameters, and to reduce the AdU activity, authors reported other reversible BTKIs with good kinase selectivity and acceptable oral bioavailability. Compound 27 ( Figure 9 ) was the most interesting; like the previous compound, compound 26b , it is characterized by a carboxylic function and inhibits BTKs with IC 50 value of 1 nM, with reduced side effects [ 99 ].…”

Section: Recent Advances In Btkismentioning

confidence: 99%

The Development of BTK Inhibitors: A Five-Year Update

et al. 2021

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Bruton’s tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia. This review is focused on compounds that have appeared in the literature from 2017 that are able to block BTK in an irreversible or reversible manner; also, new promising tunable irreversible inhibitors, as well as PROTAC molecules, have been reported. This summary could improve the knowledge of the chemical diversity of BTKIs and provide information for future studies, particularly from the medicinal chemistry point of view. Data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using “BTK” and “BTK inhibitors” as keywords.

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Discovery of novel BTK inhibitors with carboxylic acids

Cited by 18 publications

References 14 publications

Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry

Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry

Cubanes in Medicinal Chemistry

The Development of BTK Inhibitors: A Five-Year Update

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