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Discovery of structural diverse reversible BTK inhibitors utilized to develop a novel in vivo CD69 and CD86 PK/PD
George H Vandeveer1, Robert M Arduini2, Darren P Baker2
1Medicinal Chemistry, Cambridge, MA 02142, USA.
Abstract:
For the past two decades, BTK a tyrosine kinase and member of the Tec family has been a drug target of significant interest due to its potential to selectively treat various B cell-mediated diseases such as CLL, MCL, RA, and MS. Owning to the challenges encountered in identifying drug candidates exhibiting the potency block B cell activation via BTK inhibition, the pharmaceutical industry has relied on the use of covalent/irreversible inhibitors to address this unmet medical need. Herein, we describe a medicinal chemistry campaign to identify structurally diverse reversible BTK inhibitors originating from HITS identified using a fragment base screen. The leads were optimized to improve the potency and in vivo ADME properties resulting in a structurally distinct chemical series used to develop and validate a novel in vivo CD69 and CD86 PD assay in rodents.
Insights
Researchers developed novel reversible Bruton's tyrosine kinase (BTK) inhibitors, offering a new therapeutic strategy for B cell-mediated diseases. This work also established a new rodent model for evaluating drug efficacy.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Immunology
Background:
- Bruton's tyrosine kinase (BTK) is a key target for treating B cell-mediated diseases like CLL, MCL, RA, and MS.
- Current treatments often use irreversible BTK inhibitors due to challenges in developing potent reversible options.
Purpose of the Study:
- To identify and optimize novel, structurally diverse reversible BTK inhibitors.
- To develop and validate a new in vivo pharmacodynamic (PD) assay for assessing BTK inhibitor activity in rodents.
Main Methods:
- Fragment-based screening to identify initial hits (HITS).
- Medicinal chemistry optimization of leads to enhance potency and in vivo ADME properties.
- Development and validation of a CD69 and CD86 PD assay in rodents.
Main Results:
- Identification of a novel chemical series of reversible BTK inhibitors.
- Optimization of compounds with improved potency and pharmacokinetic profiles.
- Successful development and validation of a rodent-based in vivo PD assay.
Conclusions:
- This study presents a successful medicinal chemistry campaign yielding novel reversible BTK inhibitors.
- The developed compounds and assay provide a valuable platform for future research in B cell-mediated diseases.
- Reversible BTK inhibitors represent a promising alternative therapeutic approach.
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