Optimization of Dual-tropic CXCR4/CCR5 HIV-1 Entry Inhibitors and a Market Analysis Open Access

Abstract

Entry inhibitors are generally prescribed after resistance to the first and second line of treatment for HIV-1 develops. Unlike other HIV-1 drugs, entry inhibitors provide a unique method of action that has a huge potential for growth in the HIV drug market. Currently, Maraviroc, which targets only one co-receptor of HIV, is the sole FDA approved chemokine entry inhibitor. Developing a novel dual-tropic entry inhibitor that would simultaneously inhibit both receptors, CCR5 and CXCR4, used by HIV-1 to enter immune cells, could effectively block the virus from entering a cell as well as inhibit evolution to a more virulent strain. Through computational modeling and structure-activity relationship analysis, modifications have been probed around the pyrazolo-piperidine scaffold to improve CXCR4-mediated viral entry inhibition, CCR5-mediated viral entry inhibition, and reduce non-nucleoside reverse transcriptase inhibition activity (NNRTI). Efforts have led to the development of compound 16, which exhibited sub-micromolar potency against both viral tropisms and low micromolar activity against reverse transcriptase. An economic overview of the HIV drug market and the potential market for incoming entry inhibitors, especially one that is a single agent-multiple target drug, has been provided.

Table of Contents

Table of Contents

Introduction 1

HIV Drug Market Analysis 6

Public Policies 6

Market Demand 8

Market Supply 10

Results 15

Molecular Modeling 15

Synthesis of D-ring Derivatives 18

Synthesis of Novel B-ring 25

Conclusion 28

Experimentals 29

References 38

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	BS
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Organic Health Sciences, Pharmacology
Keyword	HIV CCR5 entry inhibition pyrazole-piperidine CXCR4 entry inhibitor
Committee Chair / Thesis Advisor	Liotta, Dennis C, Emory University
Committee Members	Banerjee, Samiran, Emory University Soria, Jose, Emory University

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