Lead Identification to Clinical Candidate Selection: Drugs for Chagas Disease

Abstract

Chagas disease affects 8 million people worldwide and remains a main cause of death due to heart failure in Latin America. The number of cases in the United States is now estimated to be 300,000, but there are currently no Food and Drug Administration (FDA)-approved drugs available for patients with Chagas disease. To fill this gap, we have established a public-private partnership between the University of California, San Francisco and the Genomics Institute of the Novartis Research Foundation (GNF) with the goal of delivering clinical candidates to treat Chagas disease. The discovery phase, based on the screening of more than 160,000 compounds from the GNF Academic Collaboration Library, led to the identification of new anti-Chagas scaffolds. Part of the screening campaign used and compared two screening methods, including a colorimetric-based assay using Trypanosoma cruzi expressing β-galactosidase and an image-based, high-content screening (HCS) assay using the CA-I/72 strain of T. cruzi. Comparing molecules tested in both assays, we found that ergosterol biosynthesis inhibitors had greater potency in the colorimetric assay than in the HCS assay. Both assays were used to inform structure-activity relationships for antiparasitic efficacy and pharmacokinetics. A new anti-T. cruzi scaffold derived from xanthine was identified, and we describe its development as lead series.

Synthesis and biological evaluation of quinoxaline di- N -oxide derivatives with in vitro trypanocidal activity

“…Neither of them is approved by the FDA. 5 The major limitation of currently available drugs is their lower antiparasitic activity in the established chronic form of the disease, which is the most prevalent presentation. On the other hand, both drugs have undesired side effects that can lead to treatment discontinuation, which for Nfx include anorexia, nausea and vomiting causing severe weight loss, insomnia and irritability, while for Bnz the most common adverse effect is urticarial dermatitis.…”

“…9, 10 Finally, a proof-of-concept study of the promising NCE E1224 was recently completed but the development of E1224 as monotherapy has been stopped and it will be considered for new combinatory regimens. 5,11,12 This background justifies the urgent need for novel and better drugs to treat both acute and chronic phases. Quinoxaline derivatives are a chemical scaffold that has showed a wide spectrum of biological activities.…”

Application of Multiplexed Pharmacokinetic Immunoassay to Quantify In Vivo Drug Forms and Coadministered Biologics

“…In addition, given complex molecule structures (e.g., bi-and multispecific biologics), a compound can have more than one 'active' moiety [22] or region responsible for biological function. To better define the structure-activity relationship, several ligand-binding formats targeting distinct regions of the molecule can help characterize if and for how long the active moiety is present in vivo [23]. From the analytical perspective in case study 1, the same standard calibrators and QC concentration levels/dilutions could be used to compare the assay performance between the multiplex PK methods to the individual MSD PK methods.…”

SMAFIRA-c: A benchmark text corpus for evaluation of approaches to relevance ranking and knowledge discovery in the biomedical domain

“…`model validation´, `target identification´, `assay development´. The model is based upon publications describing the early drug development pipeline (12)(13)(14)(15) To determine `equivalence´ of two publications reflecting two individual research projects (e.g. in vivo vs. in vitro), the stages of the projects have to be considered (e.g.…”

“…The goal was a reproducible identification of scientific entities `critical´ for determination of `equivalence´. Model building was informed by publications describing the early drug development pipeline (12)(13)(14)(15).…”