Driving Potency with Rotationally Stable Atropisomers: Discovery of Pyridopyrimidinedione-Carbazole Inhibitors of BTK

Srivastava, Anurag S.; Ko, Soo S.; Watterson, S. H.; Pattoli, Mark A.; Skala, Stacey; Cheng, Lihong; Obermeier, Mary; Vickery, Rodney D.; Discenza, Lorell; D’Arienzo, Celia; Gillooly, Kathleen M.; Taylor, Tracy; Pulicicchio, Claudine; McIntyre, Kim W.; Yip, Shiuhang; Sun, Dawn; Wu, Dauh‐Rurng; Dai, Jun; Wang, Chunlei; Zhang, Yingru; Wang, Bei; Pawluczyk, Joseph; Kempson, James; Zhao, Rulin; Hou, Xiaoping; Rampulla, Richard; Mathur, Arvind; Galella, Michael A.; Salter–Cid, Luisa; Barrish, Joel C.; Carter, Percy H.; Fura, Aberra; Burke, James R.; Tino, Joseph A.

doi:10.1021/acsmedchemlett.0c00335

Cited by 7 publications

(6 citation statements)

References 27 publications

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“…However, problems were encountered in tolerability studies across multiple species [29a] . Further structural activity development incorporated consideration of atropisomerism and ultimately led to a single atropisomer candidate, with substantial improvement in tolerability and blood potency ( 9 ) [29b] …”

Section: Atropisomerism In Medicinal Chemistrymentioning

confidence: 99%

Porphyrin Atropisomerism as a Molecular Engineering Tool in Medicinal Chemistry, Molecular Recognition, Supramolecular Assembly, and Catalysis

Maguire,

Strachan,

Norvaiša

et al. 2024

Chemistry A European J

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Porphyrin atropisomerism, which arises from restricted σ‐bond rotation between the macrocycle and a sufficiently bulky substituent, was identified in 1969 by Gottwald and Ullman in 5,10,15,20‐tetrakis(o‐hydroxyphenyl)porphyrins. Henceforth, an entirely new field has emerged utilizing this transformative tool. This review strives to explain the consequences of atropisomerism in porphyrins, the methods which have been developed for their separation and analysis and present the diverse array of applications. Porphyrins alone possess intriguing properties and a structure which can be easily decorated and molded for a specific function. Therefore, atropisomerism serves as a transformative tool, making it possible to obtain even a specific molecular shape. Atropisomerism has been thoroughly exploited in catalysis and molecular recognition yet presents both challenges and opportunities in medicinal chemistry.

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Section: Atropisomerism In Medicinal Chemistrymentioning

confidence: 99%

Porphyrin Atropisomerism as a Molecular Engineering Tool in Medicinal Chemistry, Molecular Recognition, Supramolecular Assembly, and Catalysis

Maguire,

Strachan,

Norvaiša

et al. 2024

Chemistry A European J

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“…BMS-986143 provided an ~11-fold enhancement of BTK inhibition (IC 50 = 0.26 vs. 3 nM), and a 6-fold increase in human whole blood potency (IC 50 = 90 vs. 550 nM) when compared to BMS-935177, as well as improved kinase selectivity. BMS-986143 exhibited dose-dependent inhibition of clinical disease progression in both CIA and CAIA models [ 97 ].…”

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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“…Restricting the number of accessible conformations along the axes of atropisomerism holds the potential to enhance pharmacology, optimize pharmacokinetics, improve physicochemical properties, and enhance safety profiles and toxicology. [6][7][8][9] According to a qualitative, cross-disciplinary guide, 10 atropisomers are classified into three groups based on their axial (torsional) rotation energy barriers and racemic half-life (t 1/2 ) (Figure 1). Class 1 atropisomers have rotation barriers around the chiral axis below 20 kcal/mol and racemize within nanoseconds to seconds at physiological temperatures, showing no axial chirality.…”

Section: Introductionmentioning

confidence: 99%

Bioactive atropisomers: Unraveling design strategies and synthetic routes for drug discovery

Liu,

Zhao,

Liu

et al. 2024

Medicinal Research Reviews

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Atropisomerism, an expression of axial chirality caused by limited bond rotation, is a prominent aspect within the field of medicinal chemistry. It has been shown that atropisomers of a wide range of compounds, including established FDA‐approved drugs and experimental molecules, display markedly different biological activities. The time‐dependent reversal of chirality in atropisomers poses complexity and obstacles in the process of drug discovery and development. Nonetheless, recent progress in understanding atropisomerism and enhanced characterization methods have greatly assisted medicinal chemists in the effective development of atropisomeric drug molecules. This article provides a comprehensive review of their special design thoughts, synthetic routes, and biological activities, serving as a reference for the synthesis and biological evaluation of bioactive atropisomers in the future.

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Driving Potency with Rotationally Stable Atropisomers: Discovery of Pyridopyrimidinedione-Carbazole Inhibitors of BTK

Cited by 7 publications

References 27 publications

Porphyrin Atropisomerism as a Molecular Engineering Tool in Medicinal Chemistry, Molecular Recognition, Supramolecular Assembly, and Catalysis

Porphyrin Atropisomerism as a Molecular Engineering Tool in Medicinal Chemistry, Molecular Recognition, Supramolecular Assembly, and Catalysis

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

Bioactive atropisomers: Unraveling design strategies and synthetic routes for drug discovery

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