Discovery and Evaluation of Pyrazolo[3,4-d]pyridazinone as a Potent and Orally Active Irreversible BTK Inhibitor

Abstract

The identification and lead optimization of a series of pyrazolo [3,4-d]pyridazinone derivatives are described as a novel class of potent irreversible BTK inhibitors, resulting in the discovery of compound 8. Compound 8 exhibited high potency against BTK kinase and acceptable PK profile. Furthermore, compound 8 demonstrated significant in vivo efficacy in a mouse-collagen-induced arthritis (CIA) model.

Design, synthesis, and antibacterial evaluation of a novel series of biaryloxazolidinone derivatives against Gram-positive bacteria

“…This result implied that compounds 13a-5 and 13b-6 had no major drug-drug interaction liability since IC 50 against all the 5 CYP enzymes was >10 μM. 37…”

Application of Chiral Piperidine Scaffolds in Drug Design

“…26 When the R group was a pyrrolidine (32) or a 4substituted piperidine (33), the potencies of compounds were low. But when the substitution site in the piperidine ring changed from 4 to 3 (34), the potencies of compounds improved a lot (►Table 6). Further SAR research studies discovered that introducing a phenyl at 5-position of the piperidine ring can further increase its activity, which led to 35, a potent PCAF inhibitor with a pIC 50 value of 7.4 and exceptional selectivity over the bromodomain and extraterminal domain (BET) bromodomain family (►Fig.…”

4-Aminopyrazolopyrimidine scaffold and its deformation in the design of tyrosine and serine/threonine kinase inhibitors in medicinal chemistry

“…Evaluation of the efficacy of compound 29 in a mouse collagen-induced arthritis model showed an equivalent effect to ibrutinib (10 mg kg −1 ) at a dose of 3 mg kg −1 with no significant body weight loss. 39…”