Timothy Alan Grese

Open Innovation Drug Discovery (OIDD): A Potential Path to Novel Therapeutic Chemical Space

The continued development of computational and synthetic methods has enabled the enumeration or preparation of a nearly endless universe of chemical structures. Nevertheless, the ability of this chemical universe to deliver small molecules that can both modulate biological targets and have drug-like physicochemical properties continues to be a topic of interest to the pharmaceutical industry and academic researchers alike. The chemical space described by public, commercial, in-house and virtual compound collections has been interrogated by multiple approaches including biochemical, cellular and virtual screening, diversity analysis, and in-silico profiling. However, current drugs and known chemical probes derived from these efforts are contained within a remarkably small volume of the predicted chemical space. Access to more diverse classes of chemical scaffolds that maintain the properties relevant for drug discovery is certainly needed to meet the increasing demands for pharmaceutical innovation. The Lilly Open Innovation Drug Discovery platform (OIDD) was designed to tackle barriers to innovation through the identification of novel molecules active in relevant disease biology models. In this article we will discuss several computational approaches towards describing novel, biologically active, drug-like chemical space and illustrate how the OIDD program may facilitate access to previously untapped molecules that may aid in the search for innovative pharmaceuticals.

Design and synthesis of fluorinated RXR modulators.

Fluorinated trienoic acid analogues of the RXR selective modulator 1 (LG101506) were synthesized, and tested for their ability to bind RXRalpha and activate RXR homo and heterodimers. Potency and efficacy were observed to be dependent upon the position of fluorination, and improvement in pharmacological profile was demonstrated in some cases.

Chapter 19. Estrogen Receptor Modulators: Effects in Non-Traditional Target Tissues

Publisher Summary Till date a variety of steroidal and nonsteroidal compounds that interact with the estrogen receptor (ER) have been developed as contraceptives and for the treatment of breast cancer, uterine dysfunction, and other disorders of the female reproductive system, and they have been recently reviewed. This chapter discusses primarily the effects of these estrogen receptor (ER) modulators in nonmammary tissue. The discussion here has been divided into four segments and classified compounds on the basis of their ability to mimic the effects of estrogen in skeletal and/or cardiovascular tissue and to induce uterine stimulation. This classification is consistent with the recently proposed classification on the basis of distinct DNA transcriptional profiles observed for the different classes. By far, the most investigated of the nonsteroidal ER modulators are the triphenylethylenes (TPEs). Originally investigated as contraceptives, compounds, such as tamoxifen, have been developed for the treatment of breast cancer on the basis of strong antagonism of estrogen action in mammary tissue. Only recently, the estrogen agonist activities of these compounds in the skeletal and cardiovascular systems have been researched. Although they partially antagonize the effects of estrogen on the uterus, evidence till date suggests that in the absence of estrogen the members of this structural class also tend to induce some level of uterine stimulation, hence they are classified here as partial agonists.

Benzopyran selective estrogen receptor modulators (SERMs): Pharmacological effects and structural correlation with raloxifene

Abstract Several 2,3-diarylbenzopyrans have been evaluated in an ovariectomized rat model and found to exhibit tissue selective estrogen agonist activity on bone and serum lipid parameters. A structural model that accounts for the pharmacological similarity of these benzopyrans and the benzothiophene SERM, raloxifene, is proposed.

Novel methodology for the synthesis of estrogenic and antiestrogenic isoflav-3-enes

Abstract A novel and selective method for the introduction of substituents at the 2-position of the isoflav-3-ene nucleus, utilising readily available 3-arylcoumarins as starting materials, is described. Thus, addition of a Grignard reagent to the corresponding phenyl acetal provided the desired 2-alkyl-, alkenyl-, or arylisoflav-3-enes. These compounds interact strongly with the estrogen receptor and show estrogenic or antiestrogenic effects depending upon the nature ol the 2-substituent.

Versatile raloxifene triflates

Abstract Methodology has been employed that permits the differentiation of the phenols of raloxifene. Transition metal mediated transformations of raloxifene triflates have subsequently provided a number of analogs that were evaluated further in two in vitro models predictive of estrogen receptor mediated biological activity.

Synthesis and pharmacology of 2-alkyl raloxifene analogs

Abstract A series of 2-alkyl and 2-cycloalkyl raloxifene analogs have been prepared and evaluated in both in vitro and in vivo models of estrogen/antiestrogen activity. In particular, the 2-cyclohexyl analogs show promise as potent selective estrogen-receptor modulators (SERMs).

Conversion of the phytoestrogen coumestrol into a selective estrogen receptor modulator (SERM) by attachment of an amine-containing sidechain

Abstract The naturally occurring estrogen mimetic coumestrol has been shown to stimulate proliferation of MCF-7 mammary tumor cells and to cause uterotrophic effects in ovariectomized (OVX) rats. Attachment of a basic amine-containing sidechain to C-6 of coumestrol converts this estrogen agonist into an antagonist in breast and uterine tissue, while maintaining its estrogen-like activity as a hypocholesterolemic agent.