1147422-40-9Relevant academic research and scientific papers
Novel lead generation of an anti-tuberculosis agent active against non-replicating mycobacteria: Exploring hybridization of pyrazinamide with multiple fragments
Markad, Shankar D.,Kaur, Parvinder,Kishore Reddy,Chinnapattu, Murugan,Raichurkar, Anandkumar,Nandishaiah, Radha,Panda, Manoranjan,Iyer, Pravin S.
, p. 2986 - 2992 (2015)
The key to shortening tuberculosis (TB) drug regimen lies in eliminating the reservoir of non-replicating persistent (NRP) Mycobacterium tuberculosis (Mtb). Pyrazinamide (PZA) is the only known drug used as part of a combination therapy that is believed to kill NRP Mtb and achieve sterilization. PZA is active only under low pH screening conditions. Screening and identification of NRP-active anti-TB compounds are severely limited because compounds are usually inactive under regular assay conditions. In an effort to design novel NRP-active anti-TB compounds, we used pyrazinamide as a core and hybridized it with the fragments derived from marketed drugs. One of these designs, compound 8, was a hybrid with fluoroquinolone. This compound exhibited >10 fold improvement in NRP activity under low pH condition as compared to pyrazinamide and a modest activity (0.8 log10 kill) under nutritionally starved NRP condition. Furthermore, compound 8 was active against fluoroquinolone-resistant strains and did not show any activity in a DNA supercoiling assay (gyrase inhibition), suggesting that its mechanism of action is not that of the parent fluoroquinolone. These results provide a novel avenue in the exploration of new chemotypes that are active against non-replicating Mtb.
Discovery of novel PI3-Kinase δ specific inhibitors for the treatment of rheumatoid arthritis: Taming CYP3A4 time-dependent inhibition
Safina, Brian S.,Baker, Stewart,Baumgardner, Matt,Blaney, Paul M.,Chan, Bryan K.,Chen, Yung-Hsiang,Cartwright, Matthew W.,Castanedo, Georgette,Chabot, Christine,Cheguillaume, Arnaud J.,Goldsmith, Paul,Goldstein, David M.,Goyal, Bindu,Hancox, Timothy,Handa, Raj K.,Iyer, Pravin S,Kaur, Jasmit,Kondru, Rama,Kenny, Jane R.,Krintel, Sussie L.,Li, Jun,Lesnick, John,Lucas, Matthew C.,Lewis, Cristina,Mukadam, Sophie,Murray, Jeremy,Nadin, Alan J.,Nonomiya, Jim,Padilla, Fernando,Palmer, Wylie S.,Pang, Jodie,Pegg, Neil,Price, Steve,Reif, Karin,Salphati, Laurent,Savy, Pascal A.,Seward, Eileen M.,Shuttleworth, Stephen,Sohal, Sukhjit,Sweeney, Zachary K.,Tay, Suzanne,Tivitmahaisoon, Parcharee,Waszkowycz, Bohdan,Wei, Binqing,Yue, Qin,Zhang, Chenghong,Sutherlin, Daniel P.
, p. 5887 - 5900 (2012/08/07)
PI3Kδis a lipid kinase and a member of a larger family of enzymes, PI3K class IA(α, β, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδinhibitors and describe a structural hypothesis for isoform (α, β γ?) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.
