Cardiovascular Safety Studies Research Articles

Heart failure in SAVOR-TIMI 53: The hindsight of diabetic retinopathy.

Heart failure in SAVOR-TIMI 53: The hindsight of diabetic retinopathy.

Novel tetrahydropyran-based bacterial topoisomerase inhibitors with potent anti-gram positive activity and improved safety profile.

Novel antibacterial drugs that are effective against infections caused by multidrug resistant pathogens are urgently needed. In a previous report, we have shown that tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. During the course of our optimization program, lead compound 5 was deprioritized due to adverse findings in cardiovascular safety studies. In the effort of mitigating these findings and optimizing further the pharmacological profile of this class of compounds, we have identified a subseries of tetrahydropyran-based molecules that are potent DNA gyrase and topoisomerase IV inhibitors and display excellent antibacterial activity against Gram positive pathogens, including clinically relevant resistant isolates. One representative of this class, compound 32d, elicited only weak inhibition of hERG K(+) channels and hNaV1.5 Na(+) channels, and no effects were observed on cardiovascular parameters in anesthetized guinea pigs. In vivo efficacy in animal infection models has been demonstrated against Staphylococcus aureus and Streptococcus pneumoniae strains.

Translational PK/PD modeling for cardiovascular safety assessment of drug candidates: Methods and examples in drug development

IntroductionCardiovascular toxicity is a significant cause of candidate failure in drug development. Pharmacokinetic/pharmacodynamic (PK/PD) modeling may reduce attrition by improving the understanding of the relationship between drug exposure and changes in cardiovascular endpoints. Diverse examples are discussed that elucidate how modeling can facilitate the interpretation of cardiovascular safety data in animals and enable quantitative translation of preclinical findings to man. MethodsTwelve compounds under development in diverse therapeutic areas were tested in cardiovascular safety studies in the telemetered beagle dog and cynomolgus monkey. Drug-induced changes observed in different cardiovascular endpoints (QRS complex and QTc interval of the ECG, heart rate, blood pressure, and myocardial contractility) were described by means of PK/PD modeling. A range of direct and indirect effect models were employed to characterize the plasma concentration–cardiovascular effect relationship for each compound. ResultsFor every drug candidate the proposed PK/PD models appropriately described the cardiovascular effects observed in dog and monkey. Two of the compounds subsequently reached clinical development and cardiovascular data were generated in first-in-human clinical trials. For one drug candidate, a threshold model was used to describe QTc prolongation in the monkey and man. Blood pressure changes induced by the second compound were linked to plasma exposure in dog and human via an indirect response model. In both cases it was found that translational modeling accurately predicted the human response observed during clinical development. DiscussionIn this article, a range of PK/PD models are discussed that successfully described cardiovascular safety findings in the preclinical setting. Where clinical data were available, it was found that translational modeling enabled the accurate prediction of outcomes in man and facilitated the description of the therapeutic index. PK/PD modeling is thus demonstrated as a powerful tool to aid in the quantitative cardiovascular safety assessment of drug candidates and the optimization of early clinical study protocols.

Is it Time to Transform our Treatment of Type 2 Diabetes?

This meeting comprised two sessions: the morning session centred around glucagon-like peptide-1 receptor (GLP-1R) agonists and SGLT-2 inhibitors, a new class of glucose-lowering compounds, while the afternoon session focused on new results of cardiovascular safety studies with diabetes medications, with special attention to the SAVOR-TIMI trial of saxagliptin.

Diabetes Treatment: Recent Developments

Dear Colleague, The prevalence of type 2 diabetes is increasing worldwide, particularly in developing countries, and follows the trend of lifestyle changes, “Western-style” diet, urbanization and increasing life expectancy. In 2011, nearly 26 million people in the United States and 366 million people globally had diabetes, while half of those were unaware of their condition. By 2030, the number of diabetic patients is estimated to almost double. Despite the multidisciplinary approach of diabetic patient, diabetes persists in being the leading cause of cardiovascular disease, blindness, end-stage renal disease, and non-traumatic lower limb amputations, while it is the fourth or fifth leading cause of death in developed countries. Optimal glycemic, lipid, and blood pressure control prevents the onset and retards the progression of diabetic complications. However, more than 50% of patients with diabetes need additional lowering of cardiovascular risk factors. Currently available treatment approaches for macro- and micro-vascular complications of diabetes are mostly symptomatic without an effect on underlying causes and on the natural history of the disease. The development of new etiological treatment options remains challenging. Pharmacologic treatment of hyperglycemia has changed dramatically in the last 10 years, with new drugs and drug classes becoming available. Several classes of pharmacological agents have been approved recently. Glucagon-like peptide-1 (GLP-1) agonists (exanatide and liraglutide), dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin) and selective sodium-glucose transporter-2 (SGLT-2) inhibitors (canagliflozin) are the most recently approved medications. GLP-1 agonists and DPP-4 inhibitors are placed in the second step of diabetes management algorithm as an add-on therapy to metformin. Nevertheless, clinical experience with SGLT-2 inhibitors is little and their place in the management algorithm remains to be defined. In clinical trials canagliflozin efficacy has been evaluated as monotherapy, as well as add-on combination therapy to metformin, to sulfonylureas and to insulin. The main developments during the last year are related to studies about the safety of DPP-4 inhibitors and insulin. Thus, despite growing concern over the last years that treatment with DPP-4 inhibitors is associated with increased risk of pancreatitis and pancreatic cancer, two large recently published randomized controlled clinical trials demonstrated that treatment with saxagliptin and alogliptin is not associated with an increased risk of either adverse outcome [1, 2]. Both studies were cardiovascular safety studies and found that the above DPP-4 inhibitors are not associated with either reduced or increased cardiovascular risk. Ultimately, many patients with type 2 diabetes will be treated with insulin. For the last 4 years, after the publication of 4 observational studies, there was growing concern regarding the potential link between treatment with insulin analog glargine and malignancies, especially breast cancer. Since the studies had several limitations and the results were conflicting and inconclusive, a large randomized controlled double-blind international trial was conducted. According to the published study conclusion and the new sub-analysis of the trial presented at the American Diabetes Association 2013 Scientific Session, the use of insulin analogs is not associated with an increased risk of any cancer in individuals with diabetes [3]. Even though considerable progress has been achieved over the past years, management of diabetes and its complications remains a major challenge. Until novel pharmacological agents are available for clinical practice, implementation of existing knowledge and available treatments remain the mainstay of management. After all, the best treatment is the one that gets done. The knowledge that available treatments are safe can only help the health care providers to make better plans for their patients.

Pharmacokinetic–pharmacodynamic modeling of QRS-prolongation by flecainide: Heart rate-dependent effects during sinus rhythm in conscious telemetered dogs

Introduction: The duration of the QRS interval is determined by the ion currents involved in cardiac depolarization. Class I antiarrhythmic drugs reduce cardiac excitability and conduction by inhibiting Nav1.5 channels responsible for INa, thus increasing the QRS interval. Previous studies in humans as well as in animal models have demonstrated a more pronounced effect on QRS-prolongation during higher heart rates. In the present study, the effects of the Nav1.5 inhibitor flecainide on cardiovascular parameters, were studied in the telemetered beagle dog under normal autonomic control. The heart rate dependency of QRS prolongation was characterized using pharmacokinetic–pharmacodynamic (PKPD) modeling. Methods: Four male telemetered beagle dogs were administered placebo or flecainide (100, 150 and 200mg) in a Latin square design. The QRS interval and heart rate were recorded, and blood samples were taken. Plasma concentrations of flecainide were fitted to a one compartment oral model and the intrapolated plasma concentrations were fitted to QRS and heart rate data sampled during 5h after dosing. Results: Flecainide increased the QRS interval in all dogs, whereas there were no effects on heart rate. Using the PKPD model, a statistically significant heart rate-dependent QRS prolongation was linked to individual concentration–time profiles of flecainide. Discussion: PKPD analysis of QRS interval data from unrestrained dogs with sinus rhythm can elucidate mechanisms previously only described during controlled heart rhythm. Specific questions can therefore be addressed in generically designed cardiovascular telemetry safety studies and different types of relationships between parameters can be uncovered. In addition, the present approach can be used to better characterize drug-induced QRS effects in cardiovascular dog models.

Development of a conscious rat model of cardiac output and blood pressure measurement for cardiovascular safety studies

Development of a conscious rat model of cardiac output and blood pressure measurement for cardiovascular safety studies

Role of mixed ion channel effects in the cardiovascular safety assessment of the novel anti‐MRSA fluoroquinolone JNJ‐Q2

JNJ-Q2, a novel broad-spectrum fluoroquinolone with anti-methicillin-resistant Staphylococcus aureus activity, was evaluated in a comprehensive set of non-clinical and clinical cardiovascular safety studies. The effect of JNJ-Q2 on different cardiovascular parameters was compared with that of moxifloxacin, sparfloxacin and ofloxacin. Through comparisons with these well-known fluoroquinolones, the importance of effects on compensatory ion channels to the cardiovascular safety of JNJ-Q2 was investigated. JNJ-Q2 and comparator fluoroquinolones were evaluated in the following models/test systems: hERG-transfected HEK293 cells sodium channel-transfected CHO cells, guinea pig right atria, arterially perfused rabbit left ventricular wedge preparations and in vivo studies in anaesthetized guinea pigs, anaesthetized and conscious telemetered dogs, and a thorough QT study in humans. The trend for effects of JNJ-Q2 on Tp-Te, QT, QRS and PR intervals in the non-clinical models and the plateau in QTc with increasing plasma concentration in humans are consistent with offsetting sodium and calcium channel activities that were observed in the non-clinical studies. These mixed ion channel activities result in the less pronounced or comparable increase in QTc interval for JNJ-Q2 compared with moxifloxacin and sparfloxacin despite its greater in vitro inhibition of I(Kr). Based on the non-clinical and clinical cardiovascular safety assessment, JNJ-Q2 has a safe cardiovascular profile for administration in humans with comparable or reduced potential to prolong QT intervals, compared with moxifloxacin. The results demonstrate the importance of compensatory sodium and calcium channel activity in offsetting potassium channel activity for compounds with a fluoroquinolone core.

Comprehensive analysis of cardiac arrhythmias in telemetered cynomolgus monkeys over a 6 month period

IntroductionCardiac arrhythmia findings can be a challenge to interpret and difficult to attribute to background incidence or test article treatment. Thus, there is a growing need to better understand arrhythmia incidence in the experimental animal models used to assess the cardiovascular safety of new drugs. Currently, there is little information on the frequency of spontaneous cardiac arrhythmias in the cynomolgus monkey. MethodsThis study evaluated the baseline arrhythmia rate in a group (n=19) of non-naïve (drug-free) male telemetered cynomolgus monkeys at various timepoints over a 6month period. When sampled, data were collected continuously (24hour bins over a 6month period) and the ECG waveforms analyzed for arrhythmia using a semi-automated approach with pattern recognition software. The arrhythmia data were evaluated to detect atrial and ventricular patterns, as well as changes associated with circadian rhythm. ResultsEvaluation of this data showed that cynomolgus monkeys can exhibit spontaneous arrhythmias (day cycle; means) of the following types: supraventricular premature contraction (SPC, 10.7%); escape beats (EB, 3.8%); and sinus node pause (SNP, 2.8%), with others below 2%. From the ventricular perspective, ventricular premature beats (VPB, 25.4% (day cycle mean)) were the most prevalent. Circadian analysis indicated that some arrhythmias had higher incidence during the night cycle: SNP (32.6%); EB (18.5%); atrioventricular block (AVB, 2.7%), an indication that the arrhythmia pattern is influenced by the diurnal cycle. DiscussionOverall, the data demonstrated that a variety of spontaneous arrhythmias occur at low frequency in non-treated animals, and the incidence varies between animals, and within the same animal when repeatedly sampled. Given the low incidence in normal animals, continuous ECG sampling over multiple days is needed to establish an accurate arrhythmia “fingerprint” for each animal in dedicated telemetry colonies, which could assist the interpretation of arrhythmia findings that may occur in cardiovascular safety studies.

The Safety of Incretin-Based Therapies—Review of the Scientific Evidence

Antidiabetic therapies based on potentiation of incretin action are now widely used; however, understanding of their long-term safety remains incomplete. We searched articles in PubMed for data assessing the safety of incretin-based therapies. Three major areas of interest are reviewed: incretin action in the cardiovascular system, pancreatitis, and cancer. Incretin therapies reduce weight gain, minimize hypoglycemia, decrease inflammation, and are cardioprotective in preclinical studies. However, data permitting conclusions about whether incretin therapies modify the development of cardiovascular events in humans are not available. Case reports link incretin therapies to pancreatitis, but retrospective case control studies do not associate pancreatitis with glucagon-like peptide-1 receptor (GLP-1R) agonists or dipeptidyl peptidase-4 inhibitors. Preclinical studies of pancreatitis have yielded conflicting results, and mechanisms linking incretin receptor activation to pancreatic inflammation have not yet been forthcoming. GLP-1R activation promotes C-cell hyperplasia and medullary thyroid cancer in rodents; however, long-term clinical studies of sufficient size and duration to permit conclusions regarding cancer and incretin therapeutics have not yet been completed. The available data on incretin action and incidence of cardiovascular events, pancreatitis, or cancer are not yet sufficient or robust enough to permit firm conclusions regarding associations with incretin-based therapies in humans with diabetes. The forthcoming results of long-term cardiovascular safety studies should provide more conclusive information about the safety of GLP-1R agonists and dipeptidyl peptidase-4 inhibitors in diabetic patients.

Diabetes Treatment and Cardiovascular Safety

This is the third of a series of articles based on presentations at the American Diabetes Association (ADA) 70th Scientific Sessions, held 25–29 June 2010 in Orlando, Florida, pertaining to the need for large-scale cardiovascular (CV) safety requirements for the treatment of diabetes. The term “contrarian” is defined in various ways as “a person who takes an opposing view,” as “one who rejects the majority opinion” (1), or as “an investor who goes against current market trends” (2). What might be characterized as a “contrarian” debate on diabetes discussed the new requirement for large-scale CV safety studies on all new glucose-lowering medications. There was also a discussion of an increasingly recognized issue, potential inaccuracies of capillary glucose test meters, and of point-of-care A1C testing technologies. At the symposium, Steven Nissen (Cleveland Clinic, Cleveland, OH) addressed the question of whether diabetes drugs should have a higher bar for CV safety than other drugs. He began with an acknowledgment of relationships with multiple pharmaceutical companies, although stating that all income from such went to “charity.” He then complained about the “ridiculous title for a debate,” to suggest that the outcome (presumably his) would be a foregone conclusion. He stated that “all drugs must be required to show a health outcomes benefit,” and that “diabetes drugs are being held to [a] standard that is neither greater nor less than other fields.” He acknowledged microvascular benefits of reduction in glycemia but stated that “some of the drugs that lower blood sugar actually increase the risk of macrovascular complications” and suggested this to override microvascular disease, as “CVD is the cause of death in most diabetic patients.” Furthermore, he questioned the use of biomarkers as “surrogate for real outcomes data” and termed the blood glucose concentration as simply a “biomarker.” “Blood glucose measurements,” he suggested, …

The Electro‐Mechanical window: a risk marker for Torsade de Pointes in a canine model of drug induced arrhythmias

In cardiovascular pharmacology, electrical and mechanical events can be distinguished, and the phrase 'electro-mechanical window' (EMw) describes the temporal difference between these events. We studied whether changes in EMw have potential predictive value for the occurrence of arrhythmias in fentanyl/etomidate-anaesthetized beagle (FEAB) dogs. The EMw was calculated as differences between the QT interval and QLVP(end) in FEAB dogs during atrial pacing, treatment with isoprenaline or atropine, body temperature changes and induction of Torsade de Pointes (TdP) in an LQT1 model. The electrical systole (QT interval) was shorter than the duration of the mechanical event (QLVP(end) ), providing a positive EMw. Atrial pacing, atropine or body temperature changes had no major effects on EMw, despite large changes in QT duration. However, β-adrenoceptor stimulation (with isoprenaline) decreased the EMw (from 90 to 5 ms) and in combination with HMR1556, a blocker of the slowly activating potassium current (I(Ks) ), induced a large negative EMw (-109ms) and TdP. Prevention of TdP by atenolol or verapamil was associated with a less negative EMw (-23 to -16ms). Mexiletine, a poorly effective long QT treatment, did not affect the EMw or prevent TdP induction. The EMw is a marker, other than QT prolongation, of TdP risk in the FEAB model. Therefore, we suggest examining the EMw as a risk marker in cardiovascular safety studies and as a potential biomarker to improve clinical management of long QT syndrome patients, especially in patients with borderline QT prolongation.

Utility of positive controls in assessing assay sensitivity in ICH S7B and ICH E14 guidance for evaluation of QT/QTc interval prolongation

Positive controls have often been used in nonclinical and clinical cardiovascular safety studies to evaluate the study's assay sensitivity with respect to drug-induced prolongation of the QT interval of the electrocardiogram (ECG). If the study is able to detect such QT prolongation by the control, then a finding of negative QT effect of comparable size for the test drug will constitute evidence that the test drug does not in fact prolong the QT interval by the amount of regulatory concern. Current regulatory guidance regarding QT interval prolongation includes ICH S7B (nonclinical) and ICH E14 (clinical). However, the underlying null hypothesis settings of the two documents are quite different. This paper quantitatively evaluates the utility of positive controls in nonclinical and clinical studies in which a test drug and a positive control are simultaneously assessed in a study. The results show that positive controls, when powered at 80%, can be beneficial in 58% of nonclinical QT studies with Prob(S)=0.8; when powered at 90%, positive controls can be beneficial 73% of clinical QT studies with Prob(S)=0.9, where Prob(S) represents the probability of success with no QT risk at the stage of development.

QA interval as an indirect measure of cardiac contractility in the conscious telemeterised rat: Model optimisation and evaluation

IntroductionConscious telemeterised rats are used for early assessment of cardiovascular drug safety. This paper details the surgery required to allow key cardiovascular parameters to be determined and describes how QA interval (QAI), a surrogate measure of cardiac contractility, is related to a more direct measure of cardiac contractility, dP/dtmax (LVdP/dtmax). Experimental studies examining the effect of both positive and negative inotropes are described. MethodsEight rats were surgically implanted with telemetry probes for measuring blood pressure, heart rate, activity, body temperature and ECG parameters. Initial studies focussed on evaluating surgical procedures aimed at improving the ECG signal to allow QAI quantification. Once achieved, experimental studies were undertaken with verapamil, salmeterol, milrinone or vehicle. Following treatment, data was collected for ~20 h from pair-housed animals to establish effects on QAI or LVdP/dtmax, which was measured directly from the left ventricle in a separate group of rats. ResultsThe modified ECG lead placement produced both a qualitative and quantitative improvement in ECGs. Increases in cardiac contractility (measured directly) were paralleled by a decrease in QAI (measured indirectly). Salmeterol and milrinone increased (all p<0.05) LVdP/dtmax (1942±452 and 2333±506 mmHg/s, respectively) and decreased QAI (3.5±0.54 and 2.9±0.43 ms, respectively). In contrast, the negative inotrope verapamil decreased LVdP/dtmax (–2119±300 mmHg/s) and increased QAI (4.9±0.46 ms). A statistically significant (p<0.001) linear relationship was identified between log10(QAI) and log10(LVdP/dtmax). DiscussionImprovements in ECG signal quality, resulting from refinements in surgical techniques allowed for the reliable quantification of ECG parameters. The linear relationship demonstrated between log10(QAI) and log10(LVdP/dtmax) indicates that QAI may be a useful index of cardiac contractility in routine rat cardiovascular safety studies. These limited studies support the use of QAI as an indirect measure of cardiac contractility in the rat.

Efficacy and tolerability of lumiracoxib, a highly selective cyclo-oxygenase-2 (COX2) inhibitor, in the management of pain and osteoarthritis

Lumiracoxib is a COX2 inhibitor that is highly selective, is more effective than placebo on pain in osteoarthritis (OA), with similar analgesic and anti-inflammatory effects as non-selective NSAIDs and the selective COX2 inhibitor celecoxib, has a lower incidence of upper gastrointestinal (GI) side effects in patients not taking aspirin, and a similar incidence of cardiovascular (CV) side effects compared to naproxen or ibuprofen. In the context of earlier guidelines and taking into account the GI and CV safety results of the TARGET study, lumiracoxib had secured European Medicines Agency (EMEA) approval with as indication symptomatic treatment of OA as well as short-term management of acute pain associated with primary dysmenorrhea and following orthopedic or dental surgery. In the complex clinical context of efficiency and safety of selective and non-selective COX inhibitors, its prescription and use should be based on the risk and safety profile of the patient. In addition, there is further need for long-term GI and CV safety studies and general post-marketing safety on its use in daily practice. Meanwhile, at the time of submission of this manuscript, the EMEA has withdrawn lumiracoxib throughout Europe because of the risk of serious side effects affecting the liver.

The value added by measuring myocardial contractility ‘in vivo’ in safety pharmacological profiling of drug candidates

Introduction: The objective of this study was to define the normal LVdP/dt (an index of myocardial contractility)–heart rate relationship in telemetered conscious dogs, primates and mini-pigs in our laboratory and to use these data as the basis for an additional parameter useful in drug safety evaluation. Methods: Trained dogs, Rhesus monkeys, Cynomolgus monkeys and mini-pigs (Goettinger) were equipped with radiotelemetry transmitters (ITS). Aortic pressure (AP), left ventricular pressure (LVP), a lead II ECG and body temperature could be continuously monitored. The contractility index LVdP/dtmax was derived from the LVP signal. Notocord HEM 4.1 software was used for data acquisition. For each species an LVdP/dt–heart rate relationship was evaluated using spontaneous heart rates (HR) throughout the observation period. A validation compound with positive inotropic effects (pimobendan) was then used to investigate the LVdP/dt–heart rate relationship. Results: There was a clear LVdP/dt–HR relationship in the animals tested. The inotropic agent pimobendan demonstrated the expected shift in this relationship. Discussion: Contractility of the myocardium is regulated by autonomic input activating primarily myocardial β1-adrenoceptors, but it is also affected by the “force–frequency” relationship. Compounds can therefore either directly or indirectly affect the contractility of the heart. The chronotropic effects are routinely measured in preclinical studies; however, the inotropic effects are not routinely analysed in cardiovascular safety studies. Our experience strongly recommends including this evaluation for drug candidate selection. The evaluation of LVdP/dtmax, as an index of myocardial contractile state must, however, take into account its HR-dependency.

Efficacy and safety of tamsulosin OCAS

The efficacy and safety of a new tablet formulation of tamsulosin (the oral‐controlled absorption system: OCAS®) have been assessed in several clinical trials. In a phase IIb and a phase IIIa trial, the appropriate dose of the tamsulosin tablet for clinical practice was determined. All tested doses of tamsulosin OCAS (0.4, 0.8 and 1.2 mg) improved the lower urinary symptoms (LUTS) of benign prostatic enlargement to a statistically significantly greater extent than placebo, with no differences between the doses. However, treatment with tamsulosin OCAS 0.4 mg was associated with a lower incidence of treatment‐emergent adverse events (AEs) than the 0.8 mg and 1.2 mg doses. The incidence of the two most frequently reported AEs, dizziness and abnormal ejaculation, was similar for tamsulosin OCAS 0.4 mg and placebo. As the 0.4 mg tablet had the most favourable efficacy/safety profile, it was selected as the most appropriate dose to use in further clinical research studies. In a phase IIIb trial, the 0.4 mg dose of tamsulosin OCAS improved nocturia, quality of sleep and quality of life. Cardiovascular safety studies showed that tamsulosin OCAS 0.4 mg has a better cardiovascular safety profile, even under conditions that stress the cardiovascular system and in older people. Overall, these studies confirm the assumption that the improved pharmacokinetics of tamsulosin OCAS together with tamsulosin’s α1A‐/α1D‐adrenoceptor subtype selectivity and its selective distribution to the LUT, translate into a superior safety profile.

In vitro and in vivo characterization of TC‐1827, a novel brain α4β2 nicotinic receptor agonist with pro‐cognitive activity

AbstractNicotine activates specific receptors that are cation‐permeable ionic channels located in the central and autonomous nervous systems, as well as at the neuromuscular junction. Administration of nicotine to animals and humans has been shown to enhance cognitive processes. However, side effects linked to the activation of peripheral nicotinic receptors limit the usefulness of nicotine for the treatment of cognitive disorders such as Alzheimer's disease (AD) or mild cognitive impairments (MCI). The synthesis and properties of TC‐1827, a novel metanicotine derivative that activates brain α4β2 nicotinic receptors is described. TC‐1827 has high affinity for nicotine‐labeled receptors in the cortex (Ki=34 nM), full‐agonist intrinsic activity in α4β2‐mediated neurotransmitter release studies in synaptosomes, and has no functional activity at nicotinic receptors in ganglionic or muscular cell lines. The compound enhances long‐term potentiation in hippocampal slices, a form of synaptic plasticity thought to be involved in information storage at the cellular level. In vivo studies demonstrate that TC‐1827 dose‐dependently occupies thalamic nicotinic receptors labeled with [3H]‐cytisine, increases cortical extracellular acetylcholine levels following oral administration, and enhances cognitive performance in rat and mice behavioral procedures of learning and memory. Pharmacokinetic studies in mice, rats, and monkeys indicated that TC‐1827 has good oral absorption with a first pass effect resulting in bioavailabilities of 13–65% across dose/species. Cardiovascular safety studies indicate good cardiovascular tolerability for this compound. The present data demonstrate that TC‐1827 is a selective and potent activator of brain α4β2 nicotinic receptors and is a prototypical member of a new class of compounds with potential utility in the symptomatic treatment of cognitive disorders including AD and MCI. Drug Dev. Res. 62:26–40, 2004. © 2004 Wiley‐Liss, Inc.