Preclinical Development of an Antimalarial Agent with a New Mechanism-of-Action
Abstract
We developed a series of compounds with potent activity against all human stages of the malaria parasite and excellent in vivo efficacy in mouse models of infection. We demonstrated that these compounds act via a novel mechanism-of-action (inhibition of P. falciparum cytosolic phenylalanyl tRNA synthetase, PfcPheRS) and as such this program represents an important development to combat antimalarial resistance. A lead compound, BRD5018, was identified that had potent in vivo efficacy and an improved safety profile relative to early lead compounds. In biochemical aminoacylation assays, BRD5018 strongly inhibited PfcPheRS, with high selectivity over human cPheRS. We have completed the manufacturing of GLP materials and the corresponding impurity identification studies. We also initiated preliminary dose form studies, physicochemical characterization, analytical development and salt selection studies on BRD5018. Contracts with CROs for IND-enabling preclinical safety and DMPK studies have been signed and await final approvals to initiate work. Our goals are to complete Investigational New Drug (IND)-enabling GLP studies with BRD5018 and subsequently nominate this compound as a clinical candidate for Phase I studies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2019
- Accession Number
- AD1080089
Entities
People
- B. V. Sasidhar
- Bruno Melilo
- Cindy Hon
- Hiroharu Kojima
- Massaharu Gotoda
- Raku Shinkyo
- Stuart Schreiber
- Vaishali Dixit
- Yvonne Van Gessel