Osteonecrosis of jaw is a chronic, severe bone disease that affects the maxilla and mandible. Aromatase inhibitors are a class of drugs used in postmenopausal women for the treatment of hormone receptor-positive breast cancer. This study aims to find the association of Aromatase Inhibitors by disproportionality analysis in FDA Adverse Event Reporting System (FAERS). Publicly available FAERS data was used in the study. Disproportionality analysis with Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) with 95% confidence intervals (95% CI) were calculated. A value of ROR-1.96SE>1, PRR≥2, count of co-occurrences is 3 or more, with an associated χ2 value of 4 or more were considered as a positive signal. FAERS database had a total of 15,178 reports for Osteonecrosis of jaw. Amongst which 1,061 (6.99%) reports were associated with aromatase inhibitors. The number of reports for Exemestane, Letrozole and Anastrozole were 362 (34.11%), 448 (42.22%) and 251 (23.65%) respectively. The aromatase inhibitor which had the highest risk was Exemestane with PRR 18.59 (95% CI 14.92-22.15) and ROR 18.73 (95% CI 15.14-22.60). Letrozole had a PRR of 13.37 (95% CI 8.47-25.92) and ROR 13.28 (95% CI 8.34-26.89) and Anastrozole had a PRR of 8.04 (95% CI 6.65-13.19) and ROR 8.01 (95% CI 6.64-13.37). The Likelihood ratio and Reporting rate were 536.13 and 8.02 respectively for Letrozole, 214.12 and 5.29 for Anastrozole, 523.79and 10.54 for Exemestane. The present showed an association between aromatase inhibitors and osteonecrosis of jaw, while this adverse event is not listed in the clinical trial or post-marketing data. Although a causal relation cannot be definitively proved, the number of cases reported suggests that there might be an association. Increased awareness of this risk among both prescribers and patients may help mitigate the number and severity of these adverse events.

Objectives: This study aims in the identification of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) associated with vemurafenib using disproportionality analysis of the FDA database of Adverse Event Reporting System (FAERS). Methods: Data were obtained from the public release of data in FAERS. Case/non-case method was adopted for the analysis of association between vemurafenib use and DRESS. The data mining algorithm used for the analysis was Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR). A value of ROR-1.96SE>1, PRR≥2 were considered as positive signal. Results: A total of 7,869 reports for DRESS have been reported in the FDA database. Amongst which 101 reports were associated with vemurafenib. DRESS ranked 49th among 900 vemurafenib associated adverse drug events. The mean age was 55.87 (95% CI, 52.21- 59.52) and female to male ratio was 1.466:1. A positive signal was obtained with ROR: 13.10 and PRR: 13.12. Four deaths were reported and the non-death serious reports included hospitalization, life-threatening, disability, and other serious events with 61, 11, 2 and 39 reports respectively. Linear regression analysis indicated there was a significant correlation between the PRR and time (R=0.810; p=0.027) and ROR and time (R=0.807; p=0.028). The Log Likelihood ratio for DRESS with vemurafenib was found to be 151.14 and the reporting ratio was 11.11 (Critical value-5.59). Conclusions: A positive signal was observed for vemurafenib associated DRESS, although a causal relation cannot be definitively proved. Health care professionals should be cautious about the possibility of encountering serious adverse events associated with vemurafenib and should be reported to the regulatory authorities.

The structure-activity relationships of azetidine-based DPP IV inhibitors will be discussed in detail in the following review. The azetidine-based DPP IV inhibitors can be divided into three main subtypes, the 2-cyanoazetidines, 3-fluoroazetidines and 2-ketoazetidines. These subtypes have been explored and structure-activity relationships have been established by several groups. Several compounds within each of these subtypes display sub micromolar potency against DPP IV. The most potent cyanoazetidines and ketoazetidines have large, hydrophobic amino acid groups bound to the azetidine nitrogen and display activities below 100 nM. DPP IV inhibition is not sensitive to stereochemistry at the 2-position as both 2-(R)- and 2-(S)-cyano and -keto azetidines display similar inhibitory potencies. While these "warhead"-based cyano- and ketoazetidines have the potential for covalent, bond-forming inhibition, they can also react to internally cyclize into inactive ketopiperazines and dihydroketopyrazine. Thus, chemical instability was also explored for compounds in these two subtypes and certain members of the cyanoazetidine series display aqueous stability comparable to the closely related cyanopyrrolidines. Select 3-fluoroazetidines also display inhibitory potencies below 1 microM without the propensity for cyclization and chemical instability associated with the other subseries.

A search for noncarbohydrate sLe(x) mimics led to the development of quinic acid derivatives as selectin inhibitors. At Wyeth we solved the first cocrystal structure of a small molecule, quinic acid, with E-selectin. In the cocomplex two hydroxyls of quinic acid mimic the calcium-bound fucose of the tetrasaccharide sLe(x). The X-ray structure, together with structure based computational methods, was used to design quinic acid based libraries that were synthesized and evaluated for their ability to block the interaction of sLex with P-selectin. A large number of analogues were prepared using solution-phase parallel synthesis. Selected compounds showed decrease in leukocyte rolling in the IVM mouse model. Compound 2 inhibited neutrophil influx in the murine TIP model and demonstrated good plasma exposure.

Human angiotensin type 1 receptor (hAT1R) gene is regulated by hormones, second messengers, and both pathophysiological and developmental states. The focus of the present study was to determine the role of glucose in the trans-repression of hAT1R gene transcription and to identify the functional cis-acting response element(s). Serial deletions of the hAT1R promoter region indicated that an area between -1717 and -1543 base pairs upstream of the 5' end of the cDNA sequence has a glucose responsive regulatory element (GluRE) to down-regulate the gene expression. Further analysis revealed a putative 29-bp (5'-AACTGATTTTTGTATATTGATCTTGTATT-3') repressor element located between -1582 and -1610 bp was necessary for transcriptional repression. Removal of this region from promoter construct abolished repression of the hAT1R gene transcription in human proximal tubule epithelial cells (hPTECs). Using mobility shift assays, we demonstrated DNA binding activity to the labeled repressor element in hPTEC nuclear extracts. Additional studies demonstrated increased DNA binding activity to the labeled repressor element in nuclear extracts treated with high glucose (25 mM). Southwestern analysis identified two GluRE binding proteins of 34 and 36 kDa in glucose-treated extracts. Glucose-induced activity of the repressor trans-acting factor(s) reached a maximum at 4 h, which correlated with decreased transcriptional activity of the hAT1R gene, suggesting that glucose can down-regulate the transcription of the hAT1R gene through the repressor element. Furthermore, insertion of the glucose response element into heterologous SV40 promoter (SV40) chloramphenicol acetyl transferase (CAT) vector showed orientation/distance-independent repression of SV40 promoter-mediated CAT activity in hPTECs. Our results show that the glucose response factor(s) acts as trans-acting factor(s) binding to the cis-acting repressor element in the hAT1R promoter, which may participate in the control of basal transcription as well as glucose-mediated transcriptional inhibition of the hAT1R gene.

As part of our ongoing program to explore novel structural classes of FKBP12 ligands, we herein wish to report a new class of FKBP12 ligands containing chiral bicyclic proline analogues. Details of the synthetic routes, together with preliminary biological activity, will be presented.

In this paper the synthesis and structure–activity relationships of two classes of electrophile-based DPP IV inhibitors, the ketopyrrolidines and ketoazetidines, is discussed. The in vitro potency, stability and ex vivo experiments were performed on select compounds within these series to determine their inhibitory capacity in plasma.

The selectins play a significant role in mediating cellular adhesion and thus initiating the inflammatory and cell-mediated immune responses. In an inflammatory response, the selectins mediate the rolling of leukocytes on activated endothelial cells through the recognition of carbohydrate epitopes (e.g., sialyl Lewis(x), sLe(x)). The immune response relies on constant recirculation of lymphocytes from the blood through the vascular wall into the tissues and eventually back into the blood. Carbohydrate ligands on high endothelial venules capture circulating lymphocytes via L-selectin-dependent adhesion, leading to transmigration. Although leukocyte recruitment into the tissue is an essential physiological process, uncontrolled recruitment can lead to acute or chronic disorders such as inflammation, autoimmune diseases and tissue rejection during transplantation. Therefore, the development of agents that can modulate selectin-mediated events is an attractive therapeutic area. Summarised in this article are the patents published in this area from 1999 to present.

The hypothesis that glycoprotein (GP) IIb/IIIa antagonists stimulate platelets is controversial. Here, we report the results of flow cytometric measurements of platelet activation markers in a phase I dose optimization study of Roxifiban, an orally active GP IIb/IIIa antagonist. Whole blood was collected at pre-dose and during the dosing interval directly into citrate fixative so that circulating levels of platelet activation could be assessed. P-selectin expression and fibrinogen binding of single platelets were unchanged at any of the dosing intervals compared to the pre-dose values, whereas microaggregate formation was reduced. Blood was also collected in hirudin to maintain physiological calcium concentrations and stimulated with platelet agonists to test whether GP IIb/IIIa antagonists lower the threshold for platelet activation. After stimulation with a concentration range of ADP and TRAP, P-selectin expression was not altered by Roxifiban administration compared to pre-dose levels. Fibrinogen binding and microaggregate formation were reduced by Roxifiban dosing in a dose-dependent manner. Inhibition of both parameters was retained at trough and no increase above pre-dose values was observed at any time. This study provides evidence for a dose-dependent inhibition of platelet functions by an orally active GP IIb/IIIa antagonist and does not detect paradoxical activation of platelets by a GP IIb/IIIa antagonist in humans.

Rapid computational mining of large 3D molecular databases is central to generating new drug leads. Accurate virtual screening of large 3D molecular databases requires consideration of the conformational flexibility of the ligand molecules. Ligand flexibility can be included without prohibitively increasing the search time by docking ensembles of precomputed conformers from a conformationally expanded database. A pharmacophore-based docking method whereby conformers of the same or different molecules are overlaid by their largest 3D pharmacophore and simultaneously docked by partial matches to that pharmacophore is presented. The method is implemented in DOCK 4.0.

Nonimmunosuppressant ligands, exemplified by GPI 1046 (1), for the peptidyl-prolyl isomerase FKBP12 have been found to unexpectedly possess powerful neuroprotective and neuroregenerative effects in vitro and in vivo. We have extensively explored the therapeutic utility of FKBP12 ligands based on analogues of proline and pipecolic acid. As part of our ongoing program to explore novel structural classes of FKBP12 ligands, we herein wish to report a new class of FKBP12 ligands containing aza-proline and aza-pipecolic acid analogues. Details of the synthetic studies, together with biological activity will be presented.

Peptidylprolyl isomerase cyclophilins play critical roles in a variety of biological processes. Recent findings that cyclophilins are present at high levels in the CNS and that cyclosporin A may possess neuroprotective/neurotrophic effects have prompted us to search for nonimmunosuppressant small molecule cyclophilin ligands. To this end, we report the lead identification through "virtual screening" and the synthesis of our first series of non-peptidic cyclophilin ligands, along with the preliminary biological results.

A class of poly(ADP-ribose) polymerase (PARP-1) inhibitors, the imidazobenzodiazepines, are presented in this text. Several derivatives were designed and synthesized with ionizable groups (i.e., tertiary amines) in order to promote the desired pharmaceutical characteristics for administration in ischemic injury. Within this series, several compounds have excellent in vitro potency and our computational models accurately justify the structure-activity relationships (SARs) and highlight essential hydrogen bonding residues and hydrophobic pockets within the catalytic domain of PARP-1. Administration of these compounds (5q, 17a and 17e) in the mouse model of streptozotocin-induced diabetes results in maintainance of glucose levels. Furthermore, one such inhibitor (5g, IC(50)=26 nM) demonstrated significant reduction of infarct volume in the rat model of permanent focal cerebral ischemia.