Christopher P. Holmes

THE IDENTIFICATION OF CYCLOOXYGENASE-1 INHIBITORS FROM 4-THIAZOLIDINONE COMBINATORIAL LIBRARIES

Abstract Three 4-thiazolidinone libraries, each containing up to 540 compounds, were prepared and assayed for inhibition of the enzyme cyclooxygenase-1 (COX-1). Deconvolution analysis led to the identification of a compound that is equipotent with the commercial COX-1 inhibitors ibuprofen and phenylbutazone.

Allosteric Activation of the Follicle-stimulating Hormone (FSH) Receptor by Selective, Nonpeptide Agonists

The pituitary glycoprotein hormones, luteinizing hormone and follicle-stimulating hormone (FSH), act through their cognate receptors to initiate a series of coordinated physiological events that results in germ cell maturation. Given the importance of FSH in regulating folliculogenesis and fertility, the development of FSH mimetics has been sought to treat infertility. Currently, purified and recombinant human FSH are the only FSH receptor (FSH-R) agonists available for infertility treatment. By screening unbiased combinatorial chemistry libraries, using a cAMP-responsive luciferase reporter assay, we discovered thiazolidinone agonists (EC50s = 20 μm) of the human FSH-R. Subsequent analog library screening and parallel synthesis optimization resulted in the identification of a potent agonist (EC50 = 2 nm) with full efficacy compared with FSH that was FSH-R-selective and -dependent. The compound mediated progesterone production in Y1 cells transfected with the human FSH-R (EC50 = 980 nm) and estradiol production from primary rat ovarian granulosa cells (EC50 = 10.5 nm). This and related compounds did not compete with FSH for binding to the FSH-R. Use of human FSH/thyroid-stimulating hormone (TSH) receptor chimeras suggested a novel mechanism for receptor activation through a binding site independent of the natural hormone binding site. This study is the first report of a high affinity small molecule agonist that activates a glycoprotein hormone receptor through an allosteric mechanism. The small molecule FSH receptor agonists described here could lead to an oral alternative to the current parenteral FSH treatments used clinically to induce ovarian stimulation for both in vivo and in vitro fertilization therapy.

Differing pharmacological activities of thiazolidinone analogs at the FSH receptor

The follicle-stimulating hormone is critical to reproductive success and is an important target for development of novel reproductive therapies. We have recently reported the development of thiazolidinone positive allosteric modulators of the follicle-stimulating hormone receptor. Here, we demonstrate that discrete modifications in the chemical structure of the thiazolidinone agonists produced compounds with different pharmacological properties. Positive allosteric modulators activated adenylate cyclase signaling (Gs). Using an ADP-ribosylation assay we found that both differing glycosylated variants of human FSH (hFSH) and selected thiazolidinone allosteric modulators of the FSHR induce activation of the Gi signaling pathway. Additionally, we observed that some analogs of this class could activate both pathways. These data suggest that the pharmacological activity of thiazolidinone modulators to the FSHR may be due to the ability of these compounds to induce association of the FSHR with either Gs or Gi signaling pathways in an analog-specific manner.

PTP1B inhibitors: Synthesis and evaluation of difluoro-methylenephosphonate bioisosteres on a sulfonamide scaffold

We have synthesized and evaluated a series of triaryl sulfonamide-based PTP1B inhibitors in which a difluoro-methylenephosphonate group of a potent lead has been replaced by potential bioisosteric replacements. Several mono- or di-charged compounds (8a, 8b, and 15a) were shown exhibit inhibitory activity in the low micromolar range, demonstrating the feasibility of using this approach in identifying non-phosphonate pTyr mimetics in a small molecular scaffold. These results also provide a useful indication of the relative effectiveness of these pTyr mimetics.

A highly stereoselective synthesis of davanone

Abstract Iodocyclization of the anti 4-bromobenzyl ether acetate 4f is a key step in the first stereocontrolled synthesis of the trisubstituted tetrahydrofuran davanone.

Designing better coumarin-based fluorogenic substrates for PTP1B.

As part of a program to develop better PTP1B fluorogenic substrates that more closely mimic the functionality found in the natural substrate, we have prepared and evaluated nine novel analogs of 4-methylumbelliferone phosphate (MUP) with a variety of additional groups occupying the second phosphate binding pocket.

ENCODED COMBINATORIAL CHEMISTRY : BINARY CODING USING CHEMICALLY ROBUST SECONDARY AMINE TAGS

Publisher Summary Synthetic chemical libraries produced by combinatorial synthesis have rapidly become the important tools for pharmaceutical lead discovery and compound optimization. Many of the approaches devised to prepare such libraries rely on solid-phase synthesis techniques and exploit the efficient “split/pool” method to assemble all possible combinations of a set of chemical building blocks. Elucidation of the chemical structure of biologically active library members has represented a major challenge, because the quantity of material available for chemical analysis from a complex library is frequently miniscule. A general solution to this structure elucidation problem has been proposed here that exploits a set of surrogate analytes or identifier tags that can be detected, with either greater ease or sensitivity than the chemical entities that they represent. Through their concurrent appendage to the synthesis supports, these tags provide an unambiguous record of the chemical reaction history or chronology of monomer (building block) additions to each support in the library. This method that has become known as “encoded combinatorial synthesis” has broad scope and utility, and conceptually may be applied to the construction of any collection of compounds that can be produced through a multistep scheme of synthesis on solid supports. Two conceptually different approaches to encoding a combinatorial synthesis have been described in this chapter. In the first mode, the sequence of monomer addition steps is recorded by the parallel and alternating assembly of a polymeric molecule that is itself amenable to chemical sequence analysis. In the second coding method, sets of readily identifiable markers are attached to the supports that specify the monomer coupling reaction that is visited, in which step of the ligand synthesis.

The Traceless Solid-Phase Synthesis of Organic Molecules

Publisher Summary This chapter discusses two approaches that illustrate different tactics used in the goal of synthesizing organic compounds in a traceless manner. In the first strategy, a linker and a scaffold combine synergistically to achieve a traceless synthesis of diverse substituted benzimidazole compounds and libraries. The traceless synthetic route to create such libraries delivers compounds in moderate yields but in high purity directly after cleavage from the solid support. In the second strategy, a novel linker is used in a more global fashion to synthesize target compounds by activation of chemically diverse phenols. The strategy is based on the well-known activation properties of triflates (trifluoromethanesulfonyls) that are widely used as precursors for aryl and vinyl cations due to their excellent leaving group properties. Once an oxygen atom on the phenol moiety is activated by the triflate group, it becomes possible to carry out a reductive cleavage (deoxygenating the phenol) or cross-coupling reactions. This gives rise to a variety of substituted aromatics, or olefins at the “inert” phenolic or vinyl oxygen position.