Discovery of aminopiperidine based potent & novel topoisomerase inhibitor with broad spectrum anti-bacterial activity.

Bacterial DNA gyrase and topoisomerase IV inhibition has emerged as a promising strategy for the cure of infections caused by antibiotic-resistant bacteria. The Novel Bacterial Topoisomerase Inhibitors (NBTIs) bind to a different site from that of the quinolones with novel mechanism of action. This evades the existing target-mediated bacterial resistance associated with quinolones. This article presents our efforts to identify in vitro potent and broad-spectrum antibacterial agent 4l.

Optimisation of momelotinib with improved potency and efficacy as pan-JAK inhibitor.

Dysregulated JAK-STAT signaling has been proven to be involved in several immune-mediated diseases. Several janus kinase (JAK) inhibitors have been approved for the treatment of various inflammatory and autoimmune diseases such as rheumatoid arthritis (RA), plaque psoriasis, psoriatic arthritis, inflammatory bowel disease (IBD). Here, we report the design, optimisation, synthesis and biological evaluation of momelotinib analogues (a pyrimidine based JAK inhibitor), to get pan-JAK inhibitors. Systematic structure activity relationship studies led to the discovery of compound 32, which potently inhibited JAK1, JAK2 and JAK3. The in vivo investigation indicated that compound 32 possessed favourable pharmacokinetic properties and displayed superior anti-inflammatory efficacy than momelotinib 1. Accordingly, compound 32 was advanced into preclinical development.

Discovery of novel, potent and orally efficacious inhibitor of neutral amino acid transporter B0AT1 (SLC6A19).

Amino acid restriction by inhibition of neutral amino acid transporter, B0AT1 (SLC6A19) activity has been recently shown to improve glyceamic control by upregulating glucagon like peptide (GLP1) and fibroblast growth factor (FGF21) in mice. Hence, pharmacological inhibition of B0AT1 is expected to treat type-2 diabetes and related disorder. In this study, rationally designed trifluoromethyl sulfonyl derivatives were identified as novel, potent and orally bioavailable B0AT1 inhibitors. Compound 39 was found to be nanomolar potent (IC50: 0.035 µM) B0AT1 inhibitor with excellent pharmacokinetic profile (%F: 66) in mice and efficacious in vivo in diet induced obese (DIO) mice model.

Discovery of diaminopyrimidine-carboxamide derivatives as JAK3 inhibitors.

Selective inhibition of janus kinase (JAK) has been identified as an important strategy for the treatment of autoimmune disorders. Optimization at the C2 and C4-positions of pyrimidine ring of Cerdulatinib led to the discovery of a potent and orally bioavailable 2,4-diaminopyrimidine-5-carboxamide based JAK3 selective inhibitor (11i). A cellular selectivity study further confirmed that 11i preferentially inhibits JAK3 over JAK1, in JAK/STAT signaling pathway. Compound 11i showed good anti-arthritic activity, which could be correlated with its improved oral bioavailability. In the repeat dose acute toxicity study, 11i showed no adverse changes related to gross pathology and clinical signs, indicating that the new class JAK3 selective inhibitor could be viable therapeutic option for the treatment of rheumatoid arthritis.