Steven E Whitebread

• Higher National Certificate in Applied Biology - Analytical Biochemistry
• Researcher at Independent

Inactive ingredients may not be inert Most drug formulations comprise mainly inactive ingredients known as excipients. Excipients are tested in animal studies and do not display toxicity at allowed concentrations, but their interaction with molecular targets has not been systematically explored. Pottel et al. examined excipient activity by combinin...

Metallo-β-lactamases (MBLs), such as New Delhi metallo-β-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative bacteria to all classes of β-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobact...

The Food and Drug Administration Adverse Event Reporting System (FAERS) remains the primary source for post-marketing pharmacovigilance. The system is largely un-curated, unstandardized, and lacks a method for linking drugs to the chemical structures of their active ingredients, increasing noise and artefactual trends. To address these problems, we...

Summary of logistic regression models inspecting the dependence of reporting myocardial infarction on the use of celecoxib (Model 1: the following formula was used in R’s glm() function: has_adr~has_celecoxib), occupation of the party reporting celecoxib to cause myocardial infarction (Model 2: has_adr~has_celecoxib*occupation–occupation), time a c...

A document containing multiple sheets with reported data: groups of case_ids of reports that were found to likely correspond to the same event; monthly fractions of reported ADRs in rofecoxib reports; monthly fractions of reported ADRs in celecoxib reports; monthly fractions of reported ADRs in rosiglitazone reports; monthly fractions of reported A...

The Bayesian calculations used the program Empirica Signal and the version of FAERS offered commercially by Oracle Health Sciences. The Oracle algorithms for detection of duplicate reports and determination of generic drug names yield slightly different counts than does the data preparation method described in the present paper, although computed a...

The Food and Drug Administration Adverse Event Reporting System (FAERS) remains the primary source for post-marketing pharmacovigilance. The system is largely un-curated, unstandardized, and lacks a method for linking drugs to the chemical structures of their active ingredients, increasing noise and artefactual trends. To address these problems, we...

Medicinal chemistry poster for novel monobactam LYS228

The Food and Drug Administration Adverse Event Reporting System (FAERS) is the primary source for post-marketing pharmacovigilance. Though potentially highly useful, the database reflects reporting biases, stimulated reporting, and suffers from lack of standardization and the use of multiple drug synonyms. These biases can suggest adverse drug reac...

Over the last decade, a number of modern in vivo and in vitro methodologies and in silico tools have been developed to investigate toxicokinetic and toxicodynamic processes of chemicals, enabling an understanding of mechanism of action at different levels of biological organization from the whole organism to organ, cellular, and molecular levels. T...

Blockade of the hERG potassium channel prolongs the ventricular action potential (AP) and QT interval, and triggers early after depolarizations (EADs) and torsade de pointes (TdP) arrhythmia. Opinions differ as to the causal relationship between hERG blockade and TdP, the relative weighting of other contributing factors, definitive metrics of precl...

Treatment-related suicidal ideation and behavior (SIB) adverse events are under increasing public, legal and regulatory scrutiny. Prospective assessment of SIB is emerging as a challenging safety requirement by health authorities for the development of drugs but the underlying risk factors remain ill defined. To help with the understanding of risk...

FAERS is a postmarketing reporting system of adverse drug reactions (ADRs), developed by the Food and Drug Administration and released for open access for the public. FAERS is particularly important to track side effects that have not been observed during clinical trials because of the limited number of patients, less diverse patient populations th...

In this chapter, we highlight the importance of correct translation of target-based adverse drug reaction (ADR) prediction into the clinical symptoms that are considered during preclinical and clinical regulatory and safety assessments. Thus, we explore the appropriate translation of mode of action (MoA) into symptoms classified in system organ cla...

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The existence of different binding sites for angiotensin II (Ang II) was postulated for years, but up to the early 1980s, the tools were not available to demonstrate it. Peptidic and nonpeptidic structures were subsequently developed and these helped three independent groups to arrive at the discovery of the two main angiotensin receptors at about...

Adverse drug reactions (ADRs) are associated with most drugs, often discovered late in drug development and sometimes only during extended course of clinical use. They are linked either to the therapeutic target or pathway, or could emerge as the consequence of known or unknown off-target effect(s) of a drug or drug combinations. ADRs are a major b...

Computational target prediction methods using chemical descriptors have been applied exhaustively in drug discovery to elucidate the mechanisms-of-action (MOAs) of small molecules. To predict truly novel and unexpected small molecule-target interactions, compounds must be compared by means other than their chemical structure alone. Here we investig...

Matched molecular pair analysis (MMPA) has become a major tool for analyzing large chemistry data sets for promising chemical transformations. However, the dependence of MMPA predictions on data constraints such as the number of pairs involved, experimental uncertainty, source of the experiments, and variability of the true physical effect has not...

In vitro pharmacological profiling is increasingly being used earlier in the drug discovery process to identify undesirable off-target activity profiles that could hinder or halt the development of candidate drugs or even lead to market withdrawal if discovered after a drug is approved. Here, for the first time, the rationale, strategies and method...

Discovering the unintended 'off-targets' that predict adverse drug reactions is daunting by empirical methods alone. Drugs can act on several protein targets, some of which can be unrelated by conventional molecular metrics, and hundreds of proteins have been implicated in side effects. Here we use a computational strategy to predict the activity o...

Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determin...

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We present a novel generic method to better understand the divergent activities of molecules that often occur in orthogonal assays. The newly developed simple prediction of activity differences (SPREAD) method directly aims to model and understand the differences compounds exhibit when tested in two or more assays. By transforming the activity valu...

One of the main reasons for drug failures in clinical development, or postmarket launch, is lacking or compromised safety margins at therapeutic doses. Organ toxicity with poorly defined mechanisms and adverse drug reactions associated with on- and off-target effects are the major contributors to safety-related shortfalls of many clinical drug cand...

We present a workflow that leverages data from chemogenomics based target predictions with Systems Biology databases to better understand off-target related toxicities. By analyzing a set of compounds that share a common toxic phenotype and by comparing the pathways they affect with pathways modulated by nontoxic compounds we are able to establish...

ics: 21. CIC-Workshop Meeting

High throughput screening identified a phenoxyacetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a compound with functional potency for inhibition of human eosinophil shape change and oral bioavailability in the rat.

Preclinical Safety Pharmacology (PSP) attempts to anticipate adverse drug reactions (ADRs) during early phases of drug discovery by testing compounds in simple, in vitro binding assays (that is, preclinical profiling). The selection of PSP targets is based largely on circumstantial evidence of their contribution to known clinical ADRs, inferred fro...

The cover picture shows the relation of a chemical structure (here the statin Cerivastatin) to a protein target and phenotypic observations (symbolized by a human). Statistical models for both links can be applied independently, predicting target activity and adverse reactions. Furthermore, they can also be linked, giving clues as to which targets...

This study describes a method for mining and modeling binding data obtained from a large panel of targets (in vitro safety pharmacology) to distinguish differences between promiscuous and selective compounds. Two naïve Bayes models for promiscuity and selectivity were generated and validated on a test set as well as publicly available drug database...

[C-11]ABP688 (2) has recently been demonstrated to be a useful PET tracer for in vivo imaging of the metabotropic glutamate receptors type 5 (mGluR5) in rodents. We describe here the identification and preclinical profiling of ABP688 and its tritiated version [H-3]ABP688, and show that its high affinity (K-d = 2 nM), selectivity, and pharmacokineti...

This article reviews the use of a selection of in vitro assays implemented at Novartis and intends to address exposure and safety in early drug discovery. The authors' own experience, based on a large number of 'real' drug discovery compounds, is described to reflect on what has worked, where improvement is needed and how to best use the data for d...

Sphaleroptera alpicolana (FRÖLICH 1830) is a locally common day-flying high Alpine species previously considered to occur in the German, Austrian, Swiss, Italian and French Alps, and the Pyrenees. The females have reduced wings and cannot fly. However, a study of material from the known range of the species has shown that ‘Sphaleroptera alpicolana’...

Broad-scale in vitro pharmacology profiling of new chemical entities during early phases of drug discovery has recently become an essential tool to predict clinical adverse effects. Modern, relatively inexpensive assay technologies and rapidly expanding knowledge about G-protein coupled receptors, nuclear receptors, ion channels and enzymes have ma...

In the search for aldosterone antagonists with an optimal activity profile, twelve 9α, 11-epoxy-steroids were prepared and compared with their 9α, 11α -unsubstituted analogues in terms of steroid receptor binding in vitro and electrolyte excretion in vivo. Substitution of the parent structures by an epoxy group at positions 9α, 11 resulted in margi...

Combination of structural elements from a potent Y5 antagonist (2) with thiazole fragments that exhibit weak Y5 affinities followed by lead optimisation led to the discovery of (5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino and (4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino derivatives....

Leptin decreases food intake and increases energy expenditure in rodents by inhibiting neurones in the hypothalamic arcuate nucleus. The growth hormone secretagogue (GHS) ghrelin is known to stimulate food intake and to be the endogenous ligand for the GHS-receptor, which is strongly expressed in the arcuate nucleus, like the leptin receptor (Ob-R)...

The design of a novel series of NPY-Y5 receptor antagonists is described. Key elements for the design were the identification of weak Y5 hits from a Y1 program, results from a combinatorial approach and database mining. This led to the discovery of the quinazoline 4 and the aryl-sulphonamide moiety as major components of the pharmacophore for Y5 af...

The purpose of the present study was to investigate the continuing validity of the hypothesis that leptin is a physiologically important regulator of food intake, using the human leptin mutant R128Q leptin. In a cellular proliferation assay, based on BAF-3 cells transfected with the murine ObRb receptor, R128Q leptin was shown to be devoid of agoni...

Background: AT1 angiotensin II (AT1 Ang II) receptor activation has been shown to cause increased vascular resistance in the systemic (SVR), pulmonary (PVR), and coronary vasculature which may be of particular importance in the setting of congestive heart failure (CHF). The overall goal of this study was to examine the effects of acute AT1 Ang II...

The new neuropeptide Y (NPY) Y5 receptor antagonist CGP 71683A displayed high affinity for the cloned rat NPY Y5 subtype, but > 1, 000-fold lower affinity for the cloned rat NPY Y1, Y2, and Y4 subtypes. In LMTK cells transfected with the human NPY Y5 receptor, CGP 71683A was without intrinsic activity and antagonized NPY-induced Ca2+ transients. CG...

In the literature, conflicting data on the effect of NPY Y1 antisense oligodeoxynucleotides (ODNs) on food intake have been reported, describing either an increase or a decrease in feeding in antisense-treated animals. In the present studies antisense oligodeoxynucleotides targeted to the Y1 receptor (Y1 antisense ODNs) were used to re-investigate...

Thirteen neuropeptide Y (NPY) agonists were administered intracerebroventricularly (i.c.v.) in rats (full dose-response curves) to estimate their half-effective dose (ED50) on feeding. These values were compared to their binding affinities (IC50) for rat NPY receptor subtypes Y1, Y2, Y4 and Y5 in vitro. Correlations between in vivo ED50 and in vitr...

To the Editor: The 2 articles by Spinale et al1 2 represent an important contribution by demonstrating that combination therapy with both ACE inhibitors (ACEI) and AT1 angiotensin II (Ang II) receptor blockers provided greater improvement of left ventricular function and isolated myocyte contractile processes than either therapy used alone. Altho...

AT1 receptor activation has been demonstrated to cause increased vascular resistance properties which may be of particular importance in the setting of congestive heart failure (CHF). The overall goal of this study was to examine the effects of ACE inhibition (ACEI) alone, AT1 receptor blockade alone and combined ACEI and AT1 receptor blockade on L...

Background: AT1 receptor activation has been demonstrated to cause increased vascular resistance properties which may be of particular importance in the setting of congestive heart failure (CHF). The overall goal of this study was to examine the effects of ACE inhibition (ACEI) alone, AT1 receptor blockade alone and combined ACEI and AT1 receptor b...

These studies were designed to test the hypothesis that endogenous leptin, acting within the brain plays a physiologically important role in the control of food intake in lean rats. Antibodies directed against mouse leptin were raised in rabbits. The purified IgG fractions prepared from pre-immune and immune sera were injected into the right latera...

The recently discovered rat neuropeptide Y (NPY) receptor, the Y5 subtype, has been proposed to mediate the NPY-induced feeding response and therefore plays a central role in the regulation of food intake. These conclusions were based on studies with peptidic agonists. We now report studies in which phosphothioate end-protected antisense oligodeoxy...

The goal of this study was to determine the effects of ACE inhibition (ACEI) alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade on LV function, systemic hemodynamics, and neurohormonal system activity in a model of congestive heart failure (CHF). Pigs were randomly assigned to each of 5 group...

The goal of this study was to determine the effects of ACE inhibition alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade in a model of congestive heart failure (CHF) on isolated LV myocyte function and fundamental components of the excitation-contraction coupling process. Pigs were randomly a...

Neuropeptide Y (NPY) is a powerful stimulant of food intake and is proposed to activate a hypothalamic 'feeding' receptor distinct from previously cloned Y-type receptors. This receptor was first suggested to explain a feeding response to NPY and related peptides, including NPY2-36, that differed from their activities at the Y1 receptor. Here we re...

Cardiac hypertrophy is associated with altered Ca2+ handling and may predispose to the development of LV dysfunction and cardiac failure. At the cellular level, the re-expression of ANF represents a well-established marker of myocyte hypertrophy while the decreased expression of the sarcoplasmatic reticulum (SR) Ca(2+)-ATPase is thought o play a cr...

The binding characteristics of the angiotensin AT1 receptor antagonist valsartan were investigated in different animal species and tissues. Using [125I](Sar1,Ile8) angiotensin II as radioligand, affinity constants were determined in liver and adrenal rat and marmoset, human adrenal and in rat aortic smooth muscle cells. In all tissues tested, valsa...

The data presented in this review demonstrate that valsartan is a potent, orally active, specific, and highly selective antagonist of the AT1-receptor subtype. It is poorly metabolized, does not accumulate in the body, and is rapidly excreted, mainly in the bile. It has a good safety profile with a wide window between an effective pharmacological d...

Protease nexin-1 (PN-1) is a potent inhibitor of serine proteases, such as thrombin and plasminogen activators, which is secreted into the extracellular space. Since PN-1 is induced following lesion of the sciatic nerve, the effect of substances known to accumulate at the site of injury was examined in primary cultures of Schwann cells. Among the c...

Angiotensin II (Ang II) is an essential component of the renin-angiotensin system and is partially responsible for the maintenance of hypertension. Two major receptor subtypes have been defined for Ang II and have been detected in the heart of various species. Most of the known functions of Ang II are mediated via the AT1 subtype, whereas the funct...

All the components of the renin-angiotensin system have been identified in the heart including the angiotensin II receptor subtypes AT¹ and AT² In the normal human heart, there is a decreasing receptor density from the right atrium to the left ventricle. In right atrial membranes prepared from pathological hearts, the percentage of AT¹ receptor dec...

Samples of human myometrium have been collected during pregnancy and from non-pregnant women. Binding studies revealed the presence of a 50-fold higher density of angiotensin II AT2 receptor in the non-pregnant state than during gestation. Low levels of the AT1 receptor subtype (approx. 20 fmol/mg protein) were detected in both pregnant and non-pre...

The purpose of this study was to investigate whether the selective angiotensin AT2 receptor ligands, CGP 42112B (Nic-Tyr-(N alpha-benzoyloxycarbonyl-Arg)Lys-His-Pro-Ile-OH) and PD 123319 ((s)-1-[[4-(dimethylamino)-3-methyl-phenyl]methyl]-5-(diphenylacetyl+ ++)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-pyridine-6-carboxylic acid) are agonists at angioten...

Starting from the structure of DuP-753 (I) and a 3-dimensional model of the pentapeptide Tyr-Ile-His-Pro-Ile, a series of new and highly potent antagonist has been designed where the imidazole moiety of the DuPont compd. has been replaced by an N-acylated amino acid residue. Valsartan (CGP48933) [(S)-N-valeryl-N-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl...

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The purpose of this study was to investigate the renal actions of the new selective angiotensin AT2 receptor ligands, CGP 42112B and PD 123319, in comparison to those of the AT1 receptor antagonist losartan, in the sodium-depleted, anesthetized rat. Losartan (1, 3 and 10 mg/kg i.v.) produced a dose-dependent decrease in blood pressure and renal vas...

The pharmacological profile of valsartan, (S)‐N‐valeryl‐ N ‐{[2′‐(1H‐tetrazol‐5‐yl)biphenyl‐4‐yl]‐methyl}‐valine, a potent, highly selective, and orally active antagonist at the angiotensin II (AII) AT 1 ‐receptor, was studied in vitro and in vivo. Valsartan competed with [ ¹²⁵ I]‐AII at its specific binding sites in rat aortic smooth muscle cell m...

An angiotensin II (Ang II) binding site, distinct from AT1 and AT2, has been found in cell cultures of rat aortic smooth muscle and rat glomerular mesangium. It is characterized by a high affinity for Ang II (Kd 0.75 +/- 0.13 nM) and Ang I (Ki 0.72 +/- 0.12 nM), but a very low affinity for Ang III (Ki 31 +/- 5 microM). Ang(1-7) (Ki 1.01 +/- 0.26 nM...

Membrane angiotensin II receptors were measured in trophoblastic tissues using a 2-step procedure. The first step consisted of the relative measurement performed at a fixed 125I[Sar1 Ile8]AII concentration of 0.15 nM in order to determine which tissues had a sufficient number of binding sites for studying the competition curves. The second consiste...

CGP 42112A, a potent angiotensin AT2 receptor selective ligand, was radio-iodinated and its binding characteristics compared with those of [125I]angiotensin II. In human myometrium (only AT2 expressed), binding was saturable (Kd 1.03 x 10(-10) M; Bmax 807 fmol/mg) and reversible (K+1 1.89 x 10(8) M-1.min-1; K-1 3.77 x 10(-3) min-1). The order of po...

Membrane angiotensin II receptors were measured in trophoblastic tissues using a 2-step procedure. The first step consisted of the relative measurement performed at a fixed 125I[Sar1 Ile8]AII concentration of 0.15 nM in order to determine which tissues had a sufficient number of binding sites for studying the competition curves. The second consiste...

Starting from the structure of the novel nonpeptidic angiotensin II antagonist DuP 753, a series of more rigid analogues was prepared by replacing the biphenyl part of DuP 753 with a naphthalene ring. Five different regioisomers (compounds 6a-e) were synthesized, and receptor binding in rat smooth muscle cell preparations as well as inhibition of a...

By analyzing human trophoblastic tissues at the full term of pregnancy, this study shows the highest levels of angiotensin-II (729 +/- 111 and 602 +/- 105 pg/g of tissue), angiotensin-II receptors (295 +/- 30 and 250 +/- 32 fmol/mg proteins), human placental lactogen (973 +/- 154 and 680 +/- 28 micrograms/g) and progesterone (1,501 +/- 193 and 1,07...

We have studied the effect of GTP gamma S on the affinity and binding kinetics of angiotensin II in plasma membrane particulate prepared from tissues expressing either only AT1 (human renal artery smooth muscle cells), only AT2 (human myometrium and bovine cerebellar cortex) or both angiotensin II receptor subtypes (rat adrenal glomerulosa). We als...

Angiotensin II [1-8 or 2-8] analogues and [4-8] fragments were dimerized through the amino- or carboxy-terminal groups in order to try to increase their potency as reported for other hormones. The binding affinity to the angiotensin II receptor subtypes A (A IIA) and B (A IIB) was tested and compared to the potency in rabbit aortic ring. The [2-8]...

Membrane angiotensin II receptors were measured in human placenta by means of 125I [Sar1 Ile8] All (angiotensin II antagonist) and characterized by using 2 other antagonists of angiotensin II: Dup 753 and CGP 42112A. These are specific and selective ligands which enable identification of AT1 and AT2 receptor subtypes respectively. The [Sar1 Ile8] A...

1.) Total renin, active renin, prorenin, angiotensin II, estradiol and progesterone were measured in maternal, placental and fetal blood and in trophoblastic and uterine tissues of the guinea pig. Furthermore, membrane angiotensin II receptors were measured in trophoblastic tissues. 2.) Blood and tissue concentrations of total renin, active renin,...

Membrane angiotensin II receptors were measured in human placenta by means of 125I [Sar1 Ile8] All (angiotensin II antagonist) and characterized by using 2 other antagonists of angiotensin II: Dup 753 and CGP 42112A. These are specific and selective ligands which enable identification of AT1 and AT2 receptor subtypes respectively. The [Sar1 Ile8] A...

Sarmesin, [Sar1, Tyr(Me)4]angiotensinII], has been reported to be a competitive angiotensin II (AII) receptor antagonist in rat smooth muscle preparations (Scanlon et al., (1984), Life Science 34, 317-321). In the present study, sarmesin displaced AII from its binding sites in rat aortic smooth muscle cells and in a rabbit aorta membrane preparatio...

Long-term pretreatment of rat mesangial cells with 12-O-tetradecanoylphorbol 13-acetate (TPA) down-regulated protein kinase C activity and potentiated the angiotensin II-induced inositol trisphosphate (InsP3) formation. This increased response to angiotensin II occurred without a significant change in the receptor number or Kd value of angiotensin...

Two angiotensin II receptor subtypes, A and B, have been described by means of specific and selective ligands (Biochem Biophys Res Commun 1989; 163:284-91). The present report describes the binding characteristics and the distribution of these subtypes in various rat tissues. Adrenal and uterus expressed both subtypes but in different proportions....