Arzoxifene (LY-353381): A Comprehensive Monograph on a Promising but Discontinued Selective Estrogen Receptor Modulator

1.0 Introduction and Classification

1.1 Arzoxifene as a Third-Generation Benzothiophene SERM

Arzoxifene, known by its developmental code name LY-353381, is a small molecule drug belonging to the benzothiophene class of Selective Estrogen Receptor Modulators (SERMs).[1] It was developed by Eli Lilly and Company as a "third-generation" SERM, representing a strategic effort to refine and optimize the therapeutic profile of earlier agents in its class.[3] Despite undergoing an extensive clinical development program that progressed to large-scale Phase III trials, Arzoxifene was ultimately never marketed and its development was discontinued.[1] Its history serves as a significant case study in the complexities of pharmaceutical development, particularly in translating preclinical promise into a clinically and commercially viable therapeutic.

1.2 The Rationale for Development: Seeking an "Ideal SERM" Profile

The scientific impetus behind the development of Arzoxifene was the pursuit of an "ideal SERM".[5] This concept envisions a molecule capable of exhibiting a precisely tailored, tissue-specific profile of estrogen receptor activity. The ideal profile would combine potent estrogen antagonist (anti-estrogenic) effects in the breast and endometrium, which is crucial for treating and preventing hormone-receptor-positive cancers, with beneficial estrogen agonist (pro-estrogenic) effects in other tissues. These desired agonist activities include maintaining bone mineral density to prevent osteoporosis and favorably modulating lipid metabolism to lower serum cholesterol.[7]