Lead Optimization of the 5-Phenylpyrazolopyrimidinone NPD-2975 toward Compounds with Improved Antitrypanosomal Efficacy.

Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE

Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-

Trypanocidal Agents*/pharmacology ; Trypanocidal Agents*/therapeutic use ; Trypanosomiasis, African*/drug therapy ; Antiprotozoal Agents*/therapeutic use ; Trypanosoma brucei brucei*; Animals ; Mice ; Humans ; Drug Development

Human African trypanosomiasis (HAT) still faces few therapeutic options and emerging drug resistance, stressing an urgency for novel antitrypanosomal drug discovery. Here, we describe lead optimization efforts aiming at improving antitrypanosomal efficacy and better physicochemical properties based on our previously reported optimized hit NPD-2975 (pIC 50 7.2). Systematic modification of the 5-phenylpyrazolopyrimidinone NPD-2975 led to the discovery of a R 4 -substituted analogue 31c (NPD-3519), showing higher in vitro potency (pIC 50 7.8) against Trypanosoma brucei and significantly better metabolic stability. Further, in vivo pharmacokinetic evaluation of 31c and experiments in an acute T. brucei mouse model confirmed improved oral bioavailability and antitrypanosomal efficacy at 50 mg/kg with no apparent toxicity. With good physicochemical properties, low toxicity, improved pharmacokinetic features, and in vivo efficacy, 31c may serve as a promising candidate for future drug development for HAT.

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0 (Trypanocidal Agents)
0 (Antiprotozoal Agents)

Date Created: 20240208 Date Completed: 20240223 Latest Revision: 20241002

20250114

PMC10895668

10.1021/acs.jmedchem.3c01976

38330051