Investigation of the Bridgehead Substituent of the Leading LRH-1 Agonists Open Access

Abstract

Liver Receptor Homolog-1 (LRH-1) is a nuclear receptor of the NR5A class and has been implicated in several disease states, most importantly type 2 diabetes (T2D), and colitis. As a result, the receptor is an attractive therapeutic target and great attention has been given to developing a synthetic modulator for LRH-1. Agonists developed in the Jui lab effectively activate and bind to the receptor (2-fold increases in LRH-1activation levels and low nanomolar binding constants), however, they are held back by their hydrophobicity and biologically unstable substituents. Major modification of the agonists has been impeded by the synthetic difficulty presented by the requisite reaction to produce the characteristic bicyclic hexhydropentalene (6HP) core. We sought to improve the pharmacological traits of our compounds by 1) removing the large, lipophilic styrene, a previously required substituent and 2) modifying the anion capped alkyl tail with various carboxylate surrogates that should both increase the metabolic stability and solubility of the compounds. We successfully overcame the synthetic difficulties presented by our agonists and developed a modular route that excludes the styrene unit; however, these compounds have proven to be more viable as potential LRH-1 antagonists. Replacement of the carboxylate tail with substitutes has proven fruitful and the development of a hybrid combining the most attractive features of previous agonists and the isostere analogues is currently underway.

Table of Contents

Introduction................................1

Results and Discussion.................6

Conclusion and Future Work........14

References..................................16

Experimental..............................19

About this Master's Thesis

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School	Laney Graduate School
Department	Chemistry
Degree	M.T.S.
Submission	Master's Thesis
Language	English
Research Field	Chemistry, Organic
Keyword	Liver Receptor Homolog 1 Agonist LRH-1
Committee Chair / Thesis Advisor	Nathan Jui, Emory University
Committee Members	Dennis Liotta, Emory University Simon Blakey, Emory University

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