# Chemistry principles applied to the development of new catalytic C-H bond functionalization methods for amine and heterocycle preparation and to the design, synthesis and use of new enzyme inhibitors

> **NIH NIH R35** · YALE UNIVERSITY · 2020 · $79,529

## Abstract

Project Summary/Abstract
The discovery and development of new methods for the preparation and use of organic compounds has consid-
erable impact upon how drugs are discovered and synthesized. One overall objective of this application is the
development of catalytic C-H bond activation and carbon-carbon bond formation for the convergent assembly of
amine containing compounds present in 84% of small-molecule drugs. Methods for the preparation of the subset
of nitrogen heterocycles present in 59% of drugs are emphasized. Efficient syntheses of these compound clas-
ses will be accomplished by C-H functionalization methods. One example is stereoselective, catalytic two- and
three-component C-H bond additions to C=O/C=N bonds to provide diverse amine and alcohol products that in
situ can be transformed into more complex, drug-relevant heterocycles. New earth abundant Co(III) catalysts
will be developed and studied for these transformations. Another example is efficient syntheses of diverse pi-
peridines, the heterocycle class with the highest frequency of occurrence in drugs, by regio- and stereoselective
elaboration of highly substituted 1,2-dihydropyridines generated in situ by one step C-H bond functionaliza-
tion/electrocyclization cascades. New methods will also be achieved to prepare bridged and fused bicyclic and
multicyclic piperidines, including pharmaceutical agents. Innovative new types of reactivity will be explored in C-
H bond functionalization and subsequent transformations. These significant studies will enable the more rapid
preparation of analogs in drug discovery efforts and reduced cost and waste in drug production due to; (1) the
ubiquitous presence of C-H bonds in organic compounds, (2) the very high functional group compatibility of the
Rh and Co catalysts used, and (3) the importance of the compound classes prepared. The second overriding
objective is the development and use of potent and selective enzyme inhibitors discovered through substrate-
based fragment approaches. Orally available inhibitors of cruzain, an essential protease of the parasite respon-
sible for Chagas disease, have been developed as have near-IR quenched activity-based inhibitors of cathepsin
S for imaging in vivo. The first inhibitors of Striatal-Enriched Phosphatase (STEP), a protein tyrosine phospha-
tase (PTP) implicated in a number of neurodegenerative diseases, including Alzheimer's disease (AD), will be
advanced. Structure-based optimization will be carried out using the first x-ray structures of STEP inhibitor
complexes. Reversible covalent inhibitors developed to recapitulate known physiological means of PTP regula-
tion will also be advanced. This innovative platform for PTP inhibition has already resulted in compounds that
reverse cognitive dysfunction in AD mouse models. The substrate fragment approach will also be applied to the
increasingly prominent class of protein post-translational modification enzymes, the protein arginine deiminases
(PAD...

## Key facts

- **NIH application ID:** 10135306
- **Project number:** 3R35GM122473-04S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** JONATHAN A ELLMAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $79,529
- **Award type:** 3
- **Project period:** 2017-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135306

## Citation

> US National Institutes of Health, RePORTER application 10135306, Chemistry principles applied to the development of new catalytic C-H bond functionalization methods for amine and heterocycle preparation and to the design, synthesis and use of new enzyme inhibitors (3R35GM122473-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10135306. Licensed CC0.

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