Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes

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

doi:10.1016/j.bmcl.2020.127390

Cited by 16 publications

(14 citation statements)

References 14 publications

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“…These chemical modifications improved potency, as well as the PK profile and off-target selectivity. Two of the most active synthesized compounds, compound 29 ( Figure 9 ), showed good activity in the rat CIA model [ 101 ].…”

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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Section: Recent Advances In Btkismentioning

confidence: 99%

The Development of BTK Inhibitors: A Five-Year Update

et al. 2021

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“…The synthesis of compound 1 requires 7 steps. 12 The C-D ring junction is forged first via condensation of the intact D ring (which is itself synthesized via a three-step proce-dure with a substituted pyrazine C ring precursor). The B and A rings are subsequently attached to the C ring core via Suzuki-Miyaura and amide coupling reactions, respectively.…”

Section: Cluster Synlettmentioning

confidence: 99%

“…We recently reported a series of reversible BTK inhibitors based on an 8-amino-imidazol[1, 5- a ]pyrazine core, exemplified by compound 1 (Figure 1 ). 11 12 Compound 1 is a highly potent and selective reversible BTK inhibitor with subnanomolar IC 50 inhibition. It exhibits dose-dependent efficacy to reduce paw-thickness in the collagen-induced arthritis (CIA) model in rats, albeit, with relatively high doses due to its suboptimal PK profile.…”

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confidence: 99%

“…13 Analogues of 1 with substitution at C-3 on the D ring had been synthesized previously via de novo synthesis and had shown dramatic effects on both potency and the PK profile. 12 However, bespoke analogues of the D ring were difficult to access synthetically, and the overall route to 1 involved installing this ring at the beginning of the synthesis (Scheme 1 ). To explore the feasibility of using LSF to generate D ring analogues of 1 , compound 1 was screened against an array of porphyrin oxidation catalysts and terminal oxidants.…”

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confidence: 99%

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Late-Stage Functionalization for the Optimization of Reversible BTK Inhibitors

Krska

Tyagarajan

Guiadeen

et al. 2022

Synlett

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Late-stage functionalization (LSF) enables medicinal chemists to quickly explore structure–activity relationships (SAR) of novel analogues derived from a fully elaborated parent structure. Using several known C–H functionalization chemistries, we have systematically applied the LSF strategy to modify different regions of a Bruton’s tyrosine kinase (BTK) reversible inhibitor lead series. This approach allowed for broad SAR exploration across several key subunits of the molecule at positions that were previously difficult to explore with traditional synthesis, providing analogues with high potency and improved pharmacokinetic properties. This case study illustrates both the promise and the challenges associated with applying LSF to complex lead molecules.

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“…Furthermore, the lactam constrained compound 26 displayed better PK profile in rats with low clearance, long half-lives and high oral bioavailability relative to 25 . In a prophylactic rat model of CIA, both 25 and 26 displayed dose-dependent efficacy (1, 3, 10, and 30 mg/kg) in reducing the paw thickness [ 82 ].…”

Section: Current Development Of Btk Inhibitors For the Treatment Of Autoimmune And Inflammatory Diseasesmentioning

confidence: 99%

Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases

Zhang

Meng

2021

Molecules

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Bruton’s tyrosine kinase (BTK) plays a crucial role in B-cell receptor and Fc receptor signaling pathways. BTK is also involved in the regulation of Toll-like receptors and chemokine receptors. Given the central role of BTK in immunity, BTK inhibition represents a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. Great efforts have been made in developing BTK inhibitors for potential clinical applications in inflammatory and autoimmune diseases. This review covers the recent development of BTK inhibitors at preclinical and clinical stages in treating these diseases. Individual examples of three types of inhibitors, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors, are discussed with a focus on their structure, bioactivity and selectivity. Contrary to expectations, reversible BTK inhibitors have not yielded a significant breakthrough so far. The development of covalent, irreversible BTK inhibitors has progressed more rapidly. Many candidates entered different stages of clinical trials; tolebrutinib and evobrutinib are undergoing phase 3 clinical evaluation. Rilzabrutinib, a covalent reversible BTK inhibitor, is now in phase 3 clinical trials and also offers a promising future. An analysis of the protein–inhibitor interactions based on published co-crystal structures provides useful clues for the rational design of safe and effective small-molecule BTK inhibitors.

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Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes

Cited by 16 publications

References 14 publications

The Development of BTK Inhibitors: A Five-Year Update

The Development of BTK Inhibitors: A Five-Year Update

Late-Stage Functionalization for the Optimization of Reversible BTK Inhibitors

Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases

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