Optimisation of fenarimol series for the treatment of Chagas disease. DNDi data is made available herewith freely to third parties. Use of these data anywhere in the world is therefore not subject to any licensing terms.

SUBMISSION ID	1741
Contact Details
Provider	Drugs for Neglected Diseases initiative - DNDi
Partnership Hub Coordinator Name	BIO Ventures for Global Health 221 Main Street, Suite 1600 San Francisco, CA 94105 USA Tel: +1 415 446 94 43 partnershiphub@bvgh.org

Submission Summary
Title	Optimisation of fenarimol series for the treatment of Chagas disease. DNDi data is made available herewith freely to third parties. Use of these data anywhere in the world is therefore not subject to any licensing terms.
Executive Summary/Abstract	Fenarimol as starting point for SAR investigations aimed at improving activity against T.cruzi and developing compounds suitable for in vivo characterisation
Keywords	Trypansoma cruzi; lead optimisation; Chagas; activity; chemical series; T.cruzi; American trypanosomiasis

Disease Selection
Disease	Chagas disease (American trypanosomiasis)
Comment
Name(s) of Infectious Organism(s)	Trypanosoma cruzi
Vector(s)
Human Target Organ(s)
Mechanism of Action (MoA)
Molecular or Cellular Target Name(s)

Type of Data
Type of Data	Lead Series Optimization

LEAD SERIES OPTIMIZATION (LO) DATA SUBFIELDS
Lead Optimization Description
Strategy for Lead Series Optimization	Lead Optimization of the fenarimol series for the treatment of Chagas disease SAR studies of triaryl scaffold led to the preparation of very active, low nM, easily synthesized T. cruzi inhibitors. Physicochemical and PK profiling as part of the optimisation cycle facilitated rapid identification of compounds suitable for profiling in infected mouse models. The lead compound supressed parasitemia to negligible levels after daily dosing for 20 days. Further optimisation of medicinal chemistry parameters such as oral exposure and selectivity over the CyP3A4/5 receptor linked to adverse drug-drug interactions in man and a limitation of the 'conazole' family of human anti-fungals was limited within the triaryl framework of the initial hit. A scaffold-hopping exercise was undertaken to explore further SAR opportunities to address these issues. Replacement of one aromatic ring by a variety of cyclic amines led to the discovery of an extensive family of novel, potent T.cruzi inhibitors.
Origin of Lead Series	Diversity set of agrochemicals screened in in vitro whole cell assay;
How many Lead Series have been Optimized?	1.0
How many Lead Series Abandoned?	0.0
Reason for Abandoning
How many Lead Series Untouched?	1.0
Reason for Not Pursuing	Simple aromatic components and modular synthesis of fenarimol made it the preferential candidate for SAR investigations
LO Chemistry Description
Chemistry Approach (es) to Lead Optimization
Chemical structure(s) of Lead Series
Chemical structure(s) of most active Lead(s)
SAR Analysis Summary
Lead Candidate Criteria Section
Lead Candidate Criteria Section
Mechanism of Action (MoA)
Is the Mechanism of Action Known?	No
Collaboration Status
In house only	No
Names of
Partners	Public Private Partnerships Epichem, Murdoch University and CDCO as part of the DNDi Chagas Lead Optimisation consortium
Service Providers
Academic Centers
Public Private Partnerships
Funding Agencies
Other Collaborators
Publication/Patent Status
Proprietary Data	Yes
Publicly available Data (Reference)	http://dndi.org/open-innovation/1012-chagas-001
Patented Data (Reference)