Development of 7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives Using QSARINS Tool as BTK Inhibitors for the Treatment of Rheumatoid Arthritis.

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the joints, leading to pain, swelling, and joint deformity. Effective management of RA involves the use of disease-modifying drugs that can slow down disease progression and alleviate symptoms. Among the potential targets for RA treatment is Bruton's tyrosine kinase (BTK), which plays a crucial role in B-cell signalling and contributes to the pathogenesis of RA. QSARINS (QSAR-INSUBRIA) is software used for the development and validation of Quantitative Structure-Activity Relationship (QSAR) analysis. In the present work, this software was explored for pharmacophore optimization of the pyrrolo-pyrimidine nucleus for anti-rheumatoid activity. A series of pyrrolo-pyrimidine derivatives were used to build the QSAR models. These models were generated to identify structural features that correlate significantly with the activity. We followed the assessment of statistical parameters to ensure thorough validation of all the QSAR models. The QSAR models demonstrating better statistical performance were selected, and descriptors of these models were analysed. The results showed that the QSAR models were highly statistically robust and exhibited a strong external predictive ability. Their structural features were also deduced. This QSAR study provided crucial information about the specific molecular features that can be used for the optimization of the pharmacophores. This research provides valuable insights into the structural features essential for BTK inhibition and paves the way for the design and development of novel anti-rheumatic agents targeting BTK in RA.