Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery

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Abstract

The carbazole CBL0137 ( 1) is a lead for drug development against human African trypanosomiasis (HAT), a disease caused by Trypanosoma brucei. To advance 1 as a candidate drug, we synthesized new analogs that were evaluated for the physicochemical properties, antitrypanosome potency, selectivity against human cells, metabolism in microsomes or hepatocytes, and efflux ratios. Structure–activity/property analyses of analogs revealed eight new compounds with higher or equivalent selectivity indices ( 5j, 5t, 5v, 5w, 5y, 8d, 13i, and 22e). Based on the overall compound profiles, compounds 5v and 5w were selected for assessment in a mouse model of HAT; while 5v demonstrated a lead-like profile for HAT drug development, 5w showed a lack of efficacy. Lessons from these studies will inform further optimization of carbazoles for HAT and other indications.

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The role of ligand efficiency metrics in drug discovery.

Andrew Hopkins, György Keserű, Paul Leeson … (2014)

The judicious application of ligand or binding efficiency metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimized ligand efficiency values for their targets. Optimizing ligand efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been observed in current medicinal chemistry practice, and to increase the quality of drug candidates.

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Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties.

Travis T. Wager, X Hou, P Verhoest … (2010)

The interplay among commonly used physicochemical properties in drug design was examined and utilized to create a prospective design tool focused on the alignment of key druglike attributes. Using a set of six physicochemical parameters ((a) lipophilicity, calculated partition coefficient (ClogP); (b) calculated distribution coefficient at pH = 7.4 (ClogD); (c) molecular weight (MW); (d) topological polar surface area (TPSA); (e) number of hydrogen bond donors (HBD); (f) most basic center (pK(a))), a druglikeness central nervous system multiparameter optimization (CNS MPO) algorithm was built and applied to a set of marketed CNS drugs (N = 119) and Pfizer CNS candidates (N = 108), as well as to a large diversity set of Pfizer proprietary compounds (N = 11 303). The novel CNS MPO algorithm showed that 74% of marketed CNS drugs displayed a high CNS MPO score (MPO desirability score ≥ 4, using a scale of 0-6), in comparison to 60% of the Pfizer CNS candidates. This analysis suggests that this algorithm could potentially be used to identify compounds with a higher probability of successfully testing hypotheses in the clinic. In addition, a relationship between an increasing CNS MPO score and alignment of key in vitro attributes of drug discovery (favorable permeability, P-glycoprotein (P-gp) efflux, metabolic stability, and safety) was seen in the marketed CNS drug set, the Pfizer candidate set, and the Pfizer proprietary diversity set. The CNS MPO scoring function offers advantages over hard cutoffs or utilization of single parameters to optimize structure-activity relationships (SAR) by expanding medicinal chemistry design space through a holistic assessment approach. Based on six physicochemical properties commonly used by medicinal chemists, the CNS MPO function may be used prospectively at the design stage to accelerate the identification of compounds with increased probability of success.

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Trypanosoma brucei Parasites Occupy and Functionally Adapt to the Adipose Tissue in Mice

Sandra Trindade, Filipa Rijo-Ferreira, Tânia Carvalho … (2016)

Summary Trypanosoma brucei is an extracellular parasite that causes sleeping sickness. In mammalian hosts, trypanosomes are thought to exist in two major niches: early in infection, they populate the blood; later, they breach the blood-brain barrier. Working with a well-established mouse model, we discovered that adipose tissue constitutes a third major reservoir for T. brucei. Parasites from adipose tissue, here termed adipose tissue forms (ATFs), can replicate and were capable of infecting a naive animal. ATFs were transcriptionally distinct from bloodstream forms, and the genes upregulated included putative fatty acid β-oxidation enzymes. Consistent with this, ATFs were able to utilize exogenous myristate and form β-oxidation intermediates, suggesting that ATF parasites can use fatty acids as an external carbon source. These findings identify the adipose tissue as a niche for T. brucei during its mammalian life cycle and could potentially explain the weight loss associated with sleeping sickness.

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Author and article information

Journal

Journal ID (nlm-ta): J Med Chem

Journal ID (iso-abbrev): J Med Chem

Journal ID (publisher-id): jm

Journal ID (coden): jmcmar

Title: Journal of Medicinal Chemistry

Publisher: American Chemical Society

ISSN (Print): 0022-2623

ISSN (Electronic): 1520-4804

Publication date (Electronic): 25 January 2023

Publication date Collection: 09 February 2023

Volume: 66

Issue: 3

Pages: 1972-1989

Affiliations

[† ]Department of Chemistry and Chemical Biology, Northeastern University , Boston, Massachusetts 02115, United States

[‡ ]Department of Molecular and Cellular Biology, Kennesaw State University , Kennesaw, Georgia 30144, United States

[§ ]Center for Tropical and Emerging Global Diseases, University of Georgia , Athens, Georgia 30602, United States

[∥ ]Incuron Inc. , Buffalo, New York 14203, United States

Author notes

[* ]Email: kmensawi@ 123456kennesaw.edu .

[* ]Email: m.pollastri@ 123456notheastern.edu .

Author information

Baljinder Singh https://orcid.org/0000-0003-2828-5768

Pradip K. Gadekar https://orcid.org/0000-0002-9129-8812

Carlos E. Sanz-Rodriguez https://orcid.org/0000-0002-6759-1955

Michael P. Pollastri https://orcid.org/0000-0001-9943-7197

Article

DOI: 10.1021/acs.jmedchem.2c01767

PMC ID: 9923759

PubMed ID: 36695630

SO-VID: 4949937f-fc7e-49d9-80b0-fc9822dc70d3

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Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 31 October 2022

Funding

Funded by: National Institute of Allergy and Infectious Diseases, doi 10.13039/100000060;

Award ID: R01AI124046

Funded by: National Institute of Allergy and Infectious Diseases, doi 10.13039/100000060;

Award ID: R01AI126311

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document-id-new-14 jm2c01767

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Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery

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Most cited references 20

The role of ligand efficiency metrics in drug discovery.

Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties.

Trypanosoma brucei Parasites Occupy and Functionally Adapt to the Adipose Tissue in Mice

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