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Many tumors use tryptophan (Trp)-catabolizing enzymes such as Indoleamine/Tryptophan-2,3-dioxygenases (IDO1/TDO2) to induce an immunosuppressive environment by depleting Trp, resulting in excessive generation of kynurenine (Kyn) pathway metabolites. IDO1 inhibitors in combination with immune-checkpoint inhibitors are gaining success in multiple cancer clinical trials. This, along with accruing evidences in literature, further strengthens the dual inhibition of IDO1/TDO2 as a highly effective therapeutic prospect. Herein, we describe the discovery of fused heterocycle based analogue EPL-1410 as a novel orally active dual inhibitor of IDO1/TDO2. In the biochemical and IFNγ stimulated HeLa cell based assays, EPL-1410 inhibited human IDO1 with IC(50) values of 320 nM and 23.6 nM respectively. EPL-1410 also inhibits human TDO2 with an IC(50) of 516 nM in the biochemical assay. Further studies of EPL-1410 in various ‘in vitro ADMET' screens (e.g., Metabolic stability, plasma protein binding, hCYP inhibition, hERG, Cerep Safety Screen 44) provided an optimal metabolic stability, free drug concentration fraction and safety profile necessary to qualify it as a lead candidate. The pharmacokinetic profile of EPL-1410 showed an excellent absolute oral bioavailability (%F~100%) in mice and rats. In addition, the characterization of EPL-1410 in a battery of DMPK studies including PK profile in higher species and preliminary safety data will be discussed. EPL-1410 showed a significant dose dependent pharmacological efficacy in reducing the tumor volume in mouse syngeneic cancer models of CT-26 colon carcinoma and B16F10 melanoma. A good correlation of efficacy to biomarker (Kyn/Trp) ratio was observed in plasma, tumor draining lymph node and tumor tissue with no treatment related adverse clinical signs and body weight reduction at all doses of EPL-1410 tested. The data presented will establish EPL-1410 as a novel, orally active and potent dual inhibitor of IDO1/TDO2 with desired pharmaceutical properties for further development as a potential immuno-oncology therapeutic intervention. Citation Format: Srinivas Gullapalli, Abhijit Roychowdhury, Tushar Khaladkar, Sangameshaver Sawargave, Ravindra Janrao, Vijay Kalhapure, Ganesh Urunkar, Jayanarayan Kulathingal, Ramamohan Reddy Lekkala, Sonali Bhadra, Pankaj Kumar Singh, Krishna Anand Putta, Sonali Manwatkar, Prashant Surve, Mukund Keshav Gurjar. EPL-1410, a novel fused heterocycle based orally active dual inhibitor of IDO1/TDO2, as a potential immune-oncology therapeutic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1701.

Suzuki-Miyaura cross coupling was successfully used for C5-arylation in 4-amino-2-chloroquinoline-3-carbaldehyde using arylbornic acid and tetrakistriphenylphosphine palladium catalyst in water. Friedländer condensation reaction on 4-amino-2-chloro/2-arylquinoline-3-carbaldehyde and aromatic ketones gave novel aryl and diarylbenzo[h] [1, 6]naphthyridines in good yields. Fluorescence quantum yields were increased by introducing C2 and C5 π donor aryl benzo[h][1, 6]naphthyridines derivatives.

magnified image Synthesis of some novel N‐substituted 2‐(chroman/6‐bromochroman‐2‐yl)‐1H‐benzimidazoles by the condensation of 3,4‐dihydro‐2H‐chroman‐2‐carboxylic acid and 6‐bromo‐3,4‐dihydro‐2H‐chroman‐2‐carboxylic acid with o‐phenylenediamine in ionic liquid (IL) [bmim]BF4 and subsequent reactions at the benzimidazole‐NH with different types of electrophiles in ILs [bmim]BF4 = 1‐butyl‐3‐methylimidazolium tetrafluoroborate, [bmim]PF6 = 1‐butyl‐3‐methylimidazolium hexafluorophosphate and [buPy]BF4 = butylpyridinium tetrafluoroborate in the presence of sodium hydroxide as a base have been reported. All the synthesized compounds were screened for their antibacterial activity. Some compounds exhibited promising antibacterial activity against Staphylococcus aureus and Salmonella typhimurium when compared to Cephalexin as a reference standard. J. Heterocyclic Chem., (2010).