Robert M. Burk

A safe and efficient method for conversion of 1,2- and 1,3-diols to cyclic carbonates utilizing triphosgene

Abstract Reaction of trisphosgene in the presence of pyridine with a variety of diols including hindered tertiary and 1,3-cyclic diols provided high yields of the corresponding cyclic carbonates.

Identification of an antagonist that selectively blocks the activity of prostamides (prostaglandin-ethanolamides) in the feline iris

The prostamides (prostaglandin‐ethanolamides) and prostaglandin (PG) glyceryl esters are biosynthesized by COX‐2 from the respective endocannabinoids anandamide and 2‐arachidonyl glycerol. Agonist studies suggest that their pharmacologies are unique and unrelated to prostanoid receptors. This concept was further investigated using antagonists.

Replacement of the carboxylic acid group of prostaglandin F2α with a hydroxyl or methoxy substituent provides biologically unique compounds

Replacement of the carboxylic acid group of PGF2α with the non‐acidic substituents hydroxyl (‐OH) or methoxy (‐OCH3) resulted in an unexpected activity profile. Although PGF2α 1‐OH and PGF2α 1‐OCH3 exhibited potent contractile effects similar to 17‐phenyl PGF2α in the cat lung parenchymal preparation, they were approximately 1000 times less potent than 17‐phenyl PGF2α in stimulating recombinant feline and human FP receptors. In human dermal fibroblasts and Swiss 3T3 cells PGF2α 1‐OH and PGF2α 1‐OCH3 produced no Ca2+ signal until a 1 μM concentration was exceeded. Pretreatment of Swiss 3T3 cells with either 1 μM PGF2α 1‐OH or PGF2α 1‐OCH3 did not attenuate Ca2+ signal responses produced by PGF2α or fluprostenol. In the rat uterus, PGF2α 1‐OH was about two orders of magnitude less potent than 17‐phenyl PGF2α whereas PGF2α 1‐OCH3 produced only a minimal effect. Radioligand binding studies on cat lung parenchymal plasma membrane preparations suggested that the cat lung parenchyma does not contain a homogeneous population of receptors that equally respond to PGF2α1‐OH, PGF2α1‐OCH3, and classical FP receptor agonists. Studies on smooth muscle preparations and cells containing DP, EP1, EP2, EP3, EP4, IP, and TP receptors indicated that the activity of PGF2α 1‐OH and PGF2α 1‐OCH3 could not be ascribed to interaction with these receptors. The potent effects of PGF2α 1‐OH and PGF2α 1‐OCH3 on the cat lung parenchyma are difficult to describe in terms of interaction with the FP or any other known prostanoid receptor.

Evidence for human thromboxane receptor heterogeneity using a novel series of 9,11-cyclic carbonate derivatives of prostaglandin F2α

1 The pharmacological activity of a novel series of 9,11‐cyclic carbonate derivatives of prostaglandin F2α (PGF2α) was investigated in various isolated smooth muscle preparations possessing different prostanoid receptor subtypes as well as in human platelets. Since subdivision of thromboxane (TP‐) receptors into vascular/smooth muscle and platelet subtypes is a controversial subject, our studies included a human smooth muscle preparation (myometrium) in addition to the widely used rat aorta and human platelets as TP‐receptor preparations. 2 Two members of that series, AGN191976 and AGN192093 were found to be highly potent and selective thromboxane‐mimetics. AGN191976 and AGN192093 contracted isolated tissues of the rat thoracic aorta with EC50 values of 0.32±0.08 and 1.30±0.53 nM, respectively. Both agonists were at least 10 times more potent than the benchmark TP‐agonist, U‐46619, in this preparation, whilst being at least 500 times less potent at other prostanoid receptors (DP, EP1, EP3, FP, IP) in vitro. 3 In human myometrial strips from pregnant and non‐pregnant donors, both AGN191976 and AGN192093 were potent contractile agonists. The rank order of potency in myometrium of AGN191976>AGN192093>U‐46619 correlated well with that in the rat aorta. In human plateletrich plasma (PRP), however, AGN191976 had potent proaggregatory activity (EC50=16.3±1.4 nM), which is a TP‐receptor‐mediated event, whereas AGN192093 was a much weaker agonist (EC50= 37.9±2.0 μm). AGN192093 did not behave as an antagonist in the platelets, since it did not antagonize platelet aggregation induced by ADP, arachidonic acid, U‐46619 or AGN191976. In human washed platelets, the activity profile of AGN191976 (EC50=4.15±0.52 nM) and AGN192093 (no aggregation up to 10 μm) was similar to that obtained in PRP. 4 The involvement of TP‐receptors was verified with the potent TP‐antagonist, SQ29548. SQ29548 (0.1 μm in myometrium; 1 μm in aorta; 1 μm and 10 μm in platelets) antagonized responses to U‐46619, AGN191976 and AGN192093 as expected. 5 In conclusion, AGN191976 and AGN192093, both 9,11‐cyclic carbonate derivatives of PGF2α, were found to be highly potent and selective thromboxane‐mimetics in rat vascular and human myometrial smooth muscle. However, only AGN 191976 was a potent agonist at TP‐receptors in human platelets. The differential activity of AGN192093 on TP‐receptor‐mediated events in platelets and smooth muscle provides further evidence for a subdivision of TP‐receptors. AGN192093 appears to be a useful tool for the pharmacological distinction of TP‐receptor subtypes.

A mild procedure for etherification of alcohols with primary alkyl halides in the presence of silver triflate

Abstract Alcohols were alkylated in good to excellent yield with primary alkyl halides by a method employing silver triflate and a non-nucleophilic amine base.

Prostaglandin ep4 antagonists

Prostaglandin antagonists, with their pharmacological effects, are well-known drugs capable of treating widely diffused illnesses, including pain and inflammation disorders. In recent years, a major research focus has been devoted to the identification of agents able to selectively antagonize each receptor with which prostaglandins interact. This review attempts to give a broad overview of molecules capable of selectively blocking the prostaglandin PGE2 EP4 receptor. Further therapeutic applications and uses have also been disccussed, including the first drug candidate to have reached clinical trials within the last few years.

A Comparative Study of Thromboxane (TP) Receptor Mimetics and Antagonists on Isolated Human Umbilical Artery and Myometrium

Pickles (1967) proposed that up to four different prostanoid types existed. Coleman et al. (1984) developed a working classification for the prostanoid receptors and since then there has been some debate concerning heterogeneity of each receptor. Following on from these studies, extensive work has led to systematic prostanoid receptor classification. The present prostanoid receptor classification is a simple systematic working hypothesis whereby each of the natural prostanoids has its own receptor termed a P receptor where it is at least ten times more potent than any of the other natural prostanoids. Thus the prostaglandin E2 (PGE2)-sensitive receptors are termed the EP-receptors, PGF2α FP-receptors, PGD2, DP-receptors, PGI2, IP receptors and the thromboxane A2 (TXA2)-sensitive receptors, TP-receptors (Kennedy et al., 1982). The thromboxane receptor (TP) has been shown to mediate constriction of airway and vascular smooth muscle as well as platelet aggregation but discussion has failed to resolve the number of receptors involved.

Prostaglandin E2 receptor subtype EP2- and EP4-regulated gene expression profiling in human ciliary smooth muscle cells

Prostanoids are an important class of intraocular pressure (IOP)-lowering antiglaucoma agents that act primarily via increased uveo-scleral aqueous humor outflow through the ciliary body. We have developed two novel PGE(2) analogs that are specific agonists for the PGE(2) receptor subtypes EP2 and EP4, respectively. To identify gene regulatory networks and key players that mediate the physiological effects observed in vivo, we performed genomewide expression studies using human ciliary smooth muscle cells. Quantitative real-time RT-PCR confirmed a largely overlapping gene expression profile subsequent to EP2 and EP4 agonist treatment, with 65 significantly regulated genes identified overall, 5 being specific for the EP2 agonist and 6 specific for the EP4 agonist. We found predicted functional cAMP-response elements in promoter regions of a large fraction of the predominantly upregulated genes, which suggests that the cAMP signaling pathway is the most important intracellular signaling pathway for these agonists in these cells. Several target genes were identified that, as part of complex regulatory networks, are implicated in tissue remodeling processes and osmoregulation (e.g., AREG, LOXL3, BMP2, AQP3) and thus may help elucidate the mechanism of action of these IOP-lowering drugs involving the uveo-scleral outflow path.

Synthesis of a novel series of 3-oxo-2,4-dioxobicyclo[3.2.1]octanes: additional evidence for two thromboxane receptor subtypes.

Abstract A series of 3-oxo-2,4-dioxobicyclo[3.2.1]octanes (1–4) was synthesized and identified as potent thromboxane (TXA2) receptor agonists. Replacement of the terminal -COOH group resulted in an unexpected change in biological activity: platelet aggregation, which typically occurs in response to TP-receptor stimulation, did not occur although potent contractile properties on vascular smooth muscle were retained.

Chapter 18 - Recent Renaissance of Prostaglandin Research

Publisher Summary This chapter discusses agonists for EP 2 , EP 4 , FP, DP, EP 1 , EP3, and EP 4 . Prostaglandins (PGs) are a class of naturally occurring hormone-like substances. PGs are derived from 20-carbon essential fatty acid lipids and as a result possess a highly oxygenated C20 backbone. They are produced in response to various stimuli in cells throughout the body and are synthesized, released and then act primarily in the vicinity of their formation. The prostanoid family of receptors includes G protein-coupled receptors with seven transmembrane domains which are ∼20–30% homologous within the family. The structures, properties and function of PG receptors have been extensively reviewed. In the early 1980s a non-definitive but “working hypothesis” classification was proposed for DP, EP, FP, IP and TP receptors according to the binding affinities, potencies and selectivities of endogenous PGD 2 , PGE 2 , PGF 2α , PGI 2 and TxA 2 . Additional pharmacological studies and molecular biology techniques later corroborated this classification and also assisted in subdivision of the Prostaglandin E (EP)-receptor into EP 1 , EP 2 , EP 3 and EP 4 . Further use of molecular biology led to development of single receptor cell-based assays and advanced the understanding of PG pharmacology, thus promoting a revival in PG biological utilities.