Abstract
Therapeutic options for rheumatoid arthritis have increased tremendously over the
last two decades. The persistent monopoly of the conventional disease-modifying anti-rheumatic
drugs over the drug platform has been taken over by a number of biologics including TNFα
inhibitors, IL-1 inhibitors, IL-6 inhibitors, and co-stimulatory signal inhibitors with better
efficacy and safety profile. However, certain factors such as lack of universal response, the need
for prolonged therapy, subcutaneous or intravenous mode of administration along with high cost
have rendered these unattractive. All this has paved the path for orally available small molecule
kinase inhibitors and ‘Tofacitinib’, the first FDA approved Janus kinase inhibitor, invaded the
market. The success of ‘Tofacitinib’ has switched on the myriad efforts for more efficacious and
safe inhibitors. Here we report the in-Silico development of novel 1, 7-dihydrodipyrrolo[2,3-
b:3’,2’-e]pyridine -3-carboxamide derivatives as JAK3 inhibitors with predicted efficacy more
than that of Tofacitinib. Although the dipyrrolopyridine analogues have already been used
for developing inhibitors for different biological conditions, the presented arrangement (1,
7-dihydrodipyrrolo[2,3-b:3’,2’-e]pyridine ) has not been explored before. Due to the linear
arrangement of its rings and characteristic position of hydrogen bond donors and acceptors, it can
accommodate the conformational changes of the binding cavity while maintaining interactions
with the ATP binding residues. The designed inhibitors show some selectivity for JAK 1 and
3 over JAK2 offering a better safety profile against the harmful effects of JAK2 inhibition.
Neelam Pery, Muhammad Imtiaz Shafiq, Nayab Batool Rizvi. (2020) In-Silico Development of 1, 7-Dihydrodipyrrolo [2,3-b:3’,2’-e] Pyridine -3-carboxamide Derivatives as Candidate Janus Kinase Inhibitors to Control Rheumatoid Arthritis, Punjab University Journal of Zoology, Volume 35, Issue 1.
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