Delving into the Latest Updates on T-229 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target-

Action-

Mechanism-

Therapeutic Areas

Infectious Diseases

Active Indication

Malaria, Falciparum

Inactive Indication-

Originator Organization

Portland State University

Active Organization

Portland State University

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Mdaki, Kennedy ; Jin, Xiannu ; Roth, Alison ; Caridha, Diana ; Liebman, Katherine M. ; Winter, Rolf W. ; Cooper, Roland A. ; Kumar, Amrendra ; Pou, Sovitj ; Li, Yuexin ; Pannone, Kristina ; Dennis, William E. ; Lee, Patricia J. ; Angutoko, Patrick ; Dodean, Rozalia A. ; Legac, Jennifer ; Dinh, Hieu T. ; Chim-Ong, Anongruk ; Rosenthal, Philip J. ; Kreutzfeld, Oriana ; Nilsen, Aaron ; Riscoe, Michael K. ; Blount, Cameron ; Kelly, Jane X. ; Orena, Stephen ; Leed, Susan ; Assimwe, Jackson ; Madejczyk, Michael S. ; Martin, Monica L. ; DeLuca, Jesse ; Zhang, Xiaowei ; Cui, Liwang ; Tibagambirwa, Innocent ; Pybus, Brandon S. ; McEnearney, Sharon ; Vuong, Chau ; Byaruhanga, Oswald ; Kancharla, Papireddy ; Kudyba, Karl ; Chetree, Ravi ; Williams, Rachel

Building from our previous lead compound T111 (1) possessing activity against both Plasmodium falciparum asexual blood-stage (ABS) and Plasmodium berghei liver-stage (LS) parasites, next-generation antimalarial acridones were systematically designed and synthesized. A large number of newly generated acridones displayed excellent antimalarial activities against both ABS and LS parasites, with feasible safety and metabolic profiles. In a high-throughput hypnozoitocidal assay using Plasmodium cynomolgi, a number of these acridones significantly inhibited schizont and hypnozoite formation in both prophylactic and radical cure-dosing modes. Notably, newer generation acridones substantially mitigated cross-resistance with atovaquone. Representative compound 28 (T229) provided full LS protection and a sustained blood-stage cure for murine P. berghei infection dosed at both 10 and 40 mg/kg/day orally. Furthermore, compound 28 demonstrated a low risk of both genotoxicity and cardiotoxicity and was highly effective against ART-resistant parasites. This study demonstrated the first and robust antirelapse LS activity from a novel acridone family.

100 Deals associated with T-229

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