Nodal staging affects adjuvant treatment choices in elderly patients with clinically node-negative, estrogen receptor-positive breast cancer.

Background: In response to Choosing Wisely recommendations that sentinel lymph node biopsy (slnb) should not be routinely performed in elderly patients with node-negative (cN0), estrogen receptor-positive (er+) breast cancer, we sought to evaluate how nodal staging affects adjuvant treatment in this population. Methods: From a prospective database, we identified patients 70 or more years of age with cN0 breast cancer treated with surgery for er+ her2-negative invasive disease during 2012-2016. We determined rates of, and factors associated with, nodal positivity (pN+), and compared the use of adjuvant radiation (rt) and systemic therapy by nodal status. Results: Of 364 patients who met the inclusion criteria, 331 (91%) underwent slnb, with 75 (23%) being pN+. Axillary node dissection was performed in 11 patients (3%). On multivariate analysis, tumour size was the only factor associated with pN+ (p = 0.007). Nodal positivity rates were 0%, 13%, 23%, 33%, and 27% for lesions preoperatively sized at 0-0.5 cm, 0.5-1 cm, 1.1-2.0 cm, 2.1-5.0 cm, and more than 5.0 cm. Compared with patients assessed as node-negative, those who were pN+ were more likely to receive axillary rt (lumpectomy: 53% vs. 1%, p < 0.001; mastectomy: 43% vs. 2%, p < 0.001), and adjuvant systemic therapy (endocrine: 82% vs. 69%; chemotherapy plus endocrine: 7% vs. 2%, p = 0.002). Conclusions: Of elderly patients with cN0 er+ breast cancer, 23% were pN+ on slnb. Size was the primary predictor of nodal status, and yet significant rates of nodal positivity were observed even in tumours preoperatively sized at 1 cm or less. The use of rt and systemic adjuvant therapies differed by nodal status, although the long-term oncologic implications require further investigation. Multidisciplinary input on a case-by-case basis should be considered before omission of slnb.

A pan-Canadian prospective study of young women with breast cancer: the rationale and protocol design for the RUBY study.

Introduction: The understanding of the biology and epidemiology of, and the optimal therapeutic strategies for, breast cancer (bca) in younger women is limited. We present the rationale, design, and initial recruitment of Reducing the Burden of Breast Cancer in Young Women (ruby), a unique national prospective cohort study designed to examine the diagnosis, treatment, quality of life, and outcomes from the time of diagnosis for young women with bca. Methods: Over a 4-year period at 33 sites across Canada, the ruby study will use a local and virtual recruitment model to enrol 1200 women with bca who are 40 years of age or younger at the time of diagnosis, before initiation of any treatment. At a minimum, comprehensive patient, tumour, and treatment data will be collected to evaluate recurrence and survival. Patients may opt to complete patient-reported questionnaires, to provide blood and tumour samples, and to be contacted for future research, forming the core dataset from which 4 subprojects evaluating genetics, lifestyle factors, fertility, and local management or delivery of care will be performed. Summary: The ruby study will be the most comprehensive repository of data, biospecimens, and patient-reported outcomes ever collected with respect to young women with bca from the time of diagnosis, enabling research unique to that population now and into the future. This research model could be used for other oncology settings in Canada.

Generalisability of Common Oncology Clinical Trial Eligibility Criteria in the Real World.

AIMS: Strict oncology clinical trial eligibility criteria can contribute to low accrual and result in poorly generalisable study findings. Using common eligibility criteria, we sought to (i) determine how many patients would be eligible versus ineligible and (ii) describe real-world patterns of treatments and outcomes between those considered trial eligible and ineligible. MATERIALS AND METHODS: The Alberta Cancer Registry was used to assemble a population-based cohort of patients diagnosed with 11 common malignancies between 2004 and 2015. We considered age >75 years, anaemia, comorbid conditions (heart disease, uncontrolled diabetes, kidney disease, liver disease) and history of a prior malignancy or immunosuppression to be exclusion criteria. Logistic regression was used to characterise the likelihood of receiving treatment. Cox regression models were constructed to determine cancer-specific and overall survival. RESULTS: We identified 125 316 cancer patients, of whom 53% were men; the median age was 66 (interquartile range 48-84) years. Approximately 38% of patients were considered trial ineligible. The most common reasons for ineligibility were advanced age (24%) and heart disease (16%). In this ineligible group, 12, 47 and 19% still underwent chemotherapy, surgery and radiotherapy, respectively. Compared with ineligible patients, eligible patients were more likely to undergo chemotherapy (odds ratio 1.98, 95% confidence interval 1.89-2.07, P < 0.0001), surgery (odds ratio 1.39, 95% confidence interval 1.32-1.46, P < 0.0001) and radiotherapy (odds ratio 1.46, 95% confidence interval 1.4-1.52, P < 0.0001). Compared with ineligible patients who did not receive treatment, those considered ineligible but who still received treatment experienced improved cancer-specific survival (hazard ratio 0.75, 95% confidence interval 0.74-0.77, P < 0.0001) and overall survival (hazard ratio 0.89, 95% confidence interval 0.87-0.90, P < 0.0001). CONCLUSIONS: A significant proportion of real-world patients are unable to participate in clinical trials due to stringent exclusion criteria, but many still receive treatment in routine practice. The eligibility criteria of oncology clinical trials should be broadened.

Taking the pulse of multidisciplinary cancer conferences for breast cancer care in Canada: A stocktake of current practice.

AIM: International guidelines highlight the importance of implementation supports and quality monitoring of multidisciplinary care for breast cancer. In Canada, Ontario has standards for formal multidisciplinary cancer conferences (MCCs), but other provinces/territories do not. This study aimed to stocktake MCCs for breast cancer in Canadian sites participating in the RUBY cohort study (Reducing the Burden of Breast Cancer in Young Women) to better understand variations in multidisciplinary care across Canada and to add to the international literature. METHODS: A cross-sectional survey was conducted with surgeons and surgical oncologists representing 34 clinical centres participating in RUBY. Questions were grouped according to: type of multidisciplinary care, implementation, function, practice, participation and presentation, operation, and demographics, and included a mix of Likert-based, tick box and open-ended questions. RESULTS: Twenty-two responses (65%) were received. 91% of respondents reported that formal MCCs are part of regular practice. However, variation exists in the supports in place for ongoing implementation of MCCs, the understanding of the functions of MCCs, and the patients presented for discussion. Results also suggest less formalized processes for MCC in provinces without practice standards. CONCLUSIONS: Response differences between Ontario and elsewhere suggest that standards for MCC and supports for their implementation make a positive difference in their operation. However, ongoing operational challenges and issues with attendance exist for all sites and suggest that along with development of practice standards, incentives for participation and further education on benefits and function of MCC may support uptake of MCCs in clinical practice.

Neoadjuvant radiotherapy followed by surgery compared with surgery alone in the treatment of retroperitoneal sarcoma: a population-based comparison.

Introduction: Retroperitoneal sarcoma (rps) encompasses a heterogeneous group of malignancies with a high recurrence rate after resection. Neoadjuvant radiotherapy (nrt) is often used in the hope of sterilizing margins and decreasing local recurrence after excision. We set out to compare local recurrence-free survival (lrfs) and overall survival (os) in patients treated with or without nrt before resection. Methods: Patients diagnosed with rps from February 1990 to October 2014 were identified in the Alberta Cancer Registry. Patients with complete gross resection of rps and no distant disease were included. Patient, tumour, treatment, and outcomes data were abstracted in a primary chart review. Baseline characteristics were compared using the Wilcoxon nonparametric test for continuous data and the Fisher exact test for dichotomous and categorical data. Survival was analyzed using Kaplan-Meier curves with log-rank test. Cox regression was performed to control for age, sex, tumour size, tumour grade, date of diagnosis, multivisceral resection, and intraoperative rupture. Results: Resection alone was performed in 62 patients, and resection after nrt, in 40. Use of nrt was associated with multivisceral resection and negative microscopic margins. On univariate analysis, nrt was associated with superior median lrfs (89.3 months vs. 28.4 months, p = 0.04) and os (119.4 months vs. 75.9 months, p = 0.04). On multivariate analysis, nrt, younger age, and lower tumour grade predicted improved lrfs and os; sex, tumour size, date of diagnosis, multivisceral resection, and tumour rupture did not. Conclusions: In this population-based study, nrt was associated with superior lrfs and os on both univariate and multivariate analysis. When feasible, nrt should be considered until a randomized controlled trial is completed.

Contralateral prophylactic mastectomy in young women with breast cancer: a population-based analysis of predictive factors and clinical impact.

Background and Objectives: Contralateral prophylactic mastectomy (cpm) has been increasingly common among women with unilateral invasive breast cancer (ibca) even though the data that support it are limited. Using a population-based cohort, the objectives of the present study were to describe factors predictive of cpm in young women (≤35 years) with ibca and to evaluate the impact of the procedure on mortality. Methods: All women diagnosed during 1994-2003 and treated with cpm were identified from the Ontario Cancer Registry. Logistic regression was used to identify patient and tumour factors associated with the use of cpm. Multivariate analyses were used to assess the effect of cpm on recurrence and mortality. Results: Of 614 women identified, 81 underwent cpm (13.2%). On multivariable analysis, factors associated with cpm included negative lymph node status, negative estrogen receptor status, and initial breast-conserving surgery with re-excision. At follow-up, breast cancer-specific mortality was similar for women who did and did not undergo cpm. Conclusions: Use of cpm in young women with ibca (compared with non-use) was not associated improved breast cancer-specific mortality. Factors found to be predictive of cpm were negative lymph node status, negative estrogen receptor status, and initial breast-conserving surgery followed by re-excision.

Comparison of international breast cancer guidelines: are we globally consistent? cancer guideline AGREEment.

BACKGROUND: Evidence-based guidelines are used in health care systems throughout the world to aid in treatment decisions and to ensure quality and consistency in patient care. In breast oncology, guidelines for care are published by several internationally recognized organizations, including those from the United States, Canada, and the United Kingdom. The present study compared clinical breast cancer guidelines from the American Society of Clinical Oncology (ASCO, United States), Cancer Care Ontario (CCO, Canada), and the National Institute for Health and Clinical Excellence (NICE, United Kingdom) to determine the quality and consistency of content across international organizations. METHODS: We searched for breast cancer guidelines published by ASCO, CCO, and NICE. Guidelines on the same theme were identified across organizations and appraised by 4 independent reviewers using the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument. Content of each guideline was also scored for consistency in overall recommendations across organizations and for consistency in cited evidence. RESULTS: The quality of breast cancer guidelines produced by the targeted organizations was consistently good in the areas of Scope and Purpose, Rigor of Development, and Clarity and Presentation, but variable in the domains of Stakeholder Involvement, Applicability, and Editorial Independence. The content of the guidelines varied slightly in the strength of their recommendations. CONCLUSIONS: Our review demonstrated consistency in quality and content for breast cancer practice guidelines published by various organizations. Future guidelines developed by these organizations should focus on how to implement and measure uptake of a guideline.

Optimal assessment of residual disease after neo-adjuvant therapy for locally advanced and inflammatory breast cancer--clinical examination, mammography, or magnetic resonance imaging?

PURPOSE: Accurate assessment of residual disease after neo-adjuvant chemotherapy (NEC) for women with locally advanced and inflammatory breast cancer (LABC) is critical for planning surgery. The study's purpose was to prospectively determine the optimal method (clinical examination (CE), mammogram (MG), and magnetic resonance imaging (MRI)) for assessing residual disease after NEC for women with LABC. METHODS: Women with LABC who received NEC and surgery were enrolled. Patient demographics, tumor size as measured by CE, MG, and MRI both before and after NEC, and final pathologic size of tumor were collected. Response to NEC was calculated using RECIST criteria. Paired t-tests and the Pearson correlation were used to compare tumor size on CE, MG, MRI, and final pathology. RESULTS: Forty-eight women with 50 LABC were recruited. Mean pre-NEC tumor size was 8.2, 5.1, and 6.2 cm on CE, MG, and MRI. Mean post-NEC tumor size was 2.4, 4.3, 3.9, and 3.6 cm on CE, MG, MRI, and final pathology. The Pearson correlation co-efficient between post-NEC measurements and pathology was 0.63 (CE), 0.15 (MG), and 0.49 (MRI). CONCLUSION: We found that there was limited correlation between the extent of residual disease after NEC for patients with LABC as assessed by CE, MG, and MRI as compared to final pathology.

Comparison of laboratory detection methods of aspirin resistance in coronary artery disease patients.

Aspirin reduces the prevalence of nonfatal myocardial infarction, stroke, and death by 25.0% in high risk group of patients with cardiovascular disease. Previous studies have estimated that about 5.5-56.8% of the population are aspirin resistant. The mechanisms of aspirin resistance (AR) have not been fully understood. We compared the detection methods for AR using traditional platelet aggregometry and VerifyNow system. One hundred and seventy-two coronary artery disease patients who had taken aspirin only or combinations with aspirin and clopidogrel for over 7 days were included. Of the 55 patients with aspirin only, aggregometer detected six AR (10.9%) and VerifyNow identified 10 AR (18.2%) cases. Among 117 patients with combined therapy, none (0.0%) and 10 (8.5%) of AR were detected by aggregometer and VerifyNow, respectively. There were six (3.4%) patients of AR defined by both methods and they all received aspirin monotherapy. Although the correlation between the aggregometry and VerifyNow was low, with defined criteria both methods gave 91.9% agreement to find AR. VerifyNow showed a higher sensitivity to detect AR. Further studies are required to biologically define AR and to alter therapy based on platelet function tests.

Evaluating the organization and delivery of breast cancer services: use of performance measures to identify knowledge gaps.

OBJECTIVES: This paper identifies gaps in our knowledge about the quality of breast cancer care in Canada to understand where programs and resources are required to enhance health services and research capacity. METHODS: A modified Delphi approach was employed involving a 15-member multidisciplinary panel of health professionals and two rounds of rating followed by deliberation to develop evidence- and consensus-based performance measures. A literature search for Canadian health services research in breast cancer was conducted based on the indicator topics. Eligible articles were identified in indexed databases of medical literature and funded research from 1995 to 2006. RESULTS: The multidisciplinary panel selected 34 indicators spanning access to services, patient outcomes, diagnosis and staging, surgery, adjuvant therapy, pathology, and follow-up care. A total of 78 articles (66 quantitative; 12 exploratory) on these topics were reviewed. Apart from two aspects of care (communication of treatment options, supportive care), the yield of Canadian breast cancer health services research did not increase subsequent to a review conducted 10 years ago which recommended greater efforts in this area. CONCLUSIONS: Research involving quantitative and qualitative methods is needed to increase our understanding about the organization and delivery of services for breast cancer diagnosis, treatment and follow-up care. Since it is unclear how to balance competing research demands, innovative strategies are required to assemble resources for health services research on breast cancer. This could include the promotion of partnerships between researchers and policy-makers across jurisdictions, and the pooling of resources between organizations, regions or networks.

Magnetic resonance imaging detects unsuspected disease in patients with invasive lobular cancer.

BACKGROUND: Predicting the extent of disease in the breasts of patients with invasive lobular cancer (ILC) can be difficult because of the limits of physical examination and standard imaging. We determined the utility of magnetic resonance imaging (MRI) in finding otherwise unsuspected cancer in the ipsilateral or contralateral breast of patients with ILC. METHODS: Through database review of all breast MRIs performed between January 1, 1999, and December 30, 2002, we identified patients with newly diagnosed ILC who underwent an MRI for extent-of-disease evaluation or contralateral screening. MRI findings separate from the primary tumor were biopsied and correlated with pathology by using MRI-guided biopsy. RESULTS: Sixty-two patients were identified. In all, 59 ipsilateral and 57 contralateral studies were performed. Suspicious lesions separate from the primary tumor were found by MRI in 38 (61%) of 62 patients. Eight patients were excluded from further analysis (seven elected mastectomy without biopsy; one had an unguided excision). Nineteen of 51 patients with an ipsilateral finding underwent MRI-guided biopsy, which revealed cancer in 11, or 22% of those imaged. Twenty of 53 patients with a contralateral finding underwent MRI-guided biopsy, which revealed cancer in 5, or 9% of those imaged. CONCLUSIONS: MRI of the breast identifies unsuspected multicentric or contralateral cancer in patients with ILC. These findings support the use of MRI in selected patients with ILC, particularly in the ipsilateral breast.

Synthesis and SAR of benzamidine factor Xa inhibitors containing a vicinally-substituted heterocyclic core.

The selective inhibition of coagulation factor Xa has emerged as an attractive strategy for the discovery of novel antithrombotic agents. Here we describe highly potent benzamidine factor Xa inhibitors based on a vicinally-substituted heterocyclic core.

Discovery of 1-[3-(aminomethyl)phenyl]-N-3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa.

Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K(i) = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.

The design and synthesis of noncovalent factor Xa inhibitors.

Thrombosis is a major cause of mortality in the industrialized world. Therefore, the control of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (fXa), the enzyme directly responsible for thrombin generation. In this review we describe our approaches in the design and synthesis of small molecule, noncovalent fXa inhibitors. Rational drug design and selective screening of our GPIIb/IIIa library afforded several lead compounds for our fXa program. Following-up the leads in the isoxazoline series led to potent fXa inhibitors such as SF303 and SK509 with only one basic group. The isoxazole series was then designed to remove the chiral center in the isoxazoline ring, and this effort led to SA862 which has subnanomolar fXa affinity. Optimizing the core structure generated a series of novel five-membered ring heterocycles substituted with benzamidine, which are potent fXa inhibitors. Further optimization in the pyrazole series resulted in the discovery of fXa inhibitors such as SN429 with picomolar fXa affinity. Efforts to improve the oral bioavailability by lowering the basicity of these compounds, while simultaneously maintaining potency against fXa, culminated in the discovery of DPC 423. DPC 423 was selected for clinical evaluation as a potent and orally bioavailable fXa inhibitor.

Nonpeptide factor Xa inhibitors II. Antithrombotic evaluation in a rabbit model of electrically induced carotid artery thrombosis.

SK549 (mol. wt. 546 Da) is a synthetic, selective inhibitor of human coagulation factor Xa (fXa) (K(i) = 0.52 nM). This study compared the antithrombotic effects of SK549 and a series of benzamidine isoxazoline fXa inhibitors with aspirin, DuP 714 (a direct thrombin inhibitor), recombinant tick anticoagulant peptide, or heparin in a rabbit model of electrically induced carotid arterial thrombosis. Compounds were infused i.v. continuously from 60 min before electrical stimulation to the end of the experiment. Values of ED(50) (dose that increases the carotid blood flow to 50% of the control) were 0.12 micromol/kg/h for SK549, 0.56 micromol/kg/h for aspirin, 0.14 micromol/kg/h for DuP 714, 0.06 micromol/kg/h for recombinant tick anticoagulant peptide, and >100 U/kg/h for heparin. The EC(50) (plasma concentration that increased blood flow to 50% of the control) for SK549 was 97 nM. Unlike aspirin and heparin, SK549 was efficacious and, at 1.5 micromol/kg/h i.v. (n = 9), maintained carotid blood flow at 87 +/- 6% of control level for greater than 90 min. Unlike heparin, SK549 inhibited ex vivo fXa activity but not ex vivo thrombin activity. There was a highly significant correlation between K(i) (fXa) and ED(50) of a series of fXa inhibitors (r = 0. 85, P <.001). Therefore, these results suggest that SK549 is a novel, potent, and effective antithrombotic agent in a rabbit model of arterial thrombosis. It is likely that SK549 exerts its antithrombotic effect through selective inhibition of fXa. Furthermore, SK549 may be clinically useful for the prevention of arterial thrombosis.

Nonpeptide factor Xa inhibitors: I. Studies with SF303 and SK549, a new class of potent antithrombotics.

A series of benzamidine isoxazoline derivatives was evaluated for their inhibitory potency against purified human factor Xa (fXa) and in a rabbit model of arteriovenous shunt thrombosis for their antithrombotic activities, expressed as K(I) and IC(50), respectively. A highly significant correlation was found between K(I) and IC(50) (r = 0.93, P <.0001). The antithrombotic effects of SF303 [mol. wt. 536; K(I): fXa, 6.3 nM; thrombin, 3,100 nM; trypsin, 110 nM; tissue plasminogen activator >20,000 nM; plasmin, 2,500 nM] and SK549 [mol. wt. 546; K(I): fXa, 0.52 nM; thrombin, 400 nM; trypsin, 45 nM; tissue plasminogen activator >33,000 nM; plasmin, 890 nM] were compared with recombinant tick anticoagulant peptide [K(I)(fXa) = 0.5 nM], DX-9065a [K(I)(fXa) = 30 nM], and heparin or low molecular weight heparin (dalteparin) in a rabbit model of arteriovenous shunt thrombosis. ID(50) values for preventing arteriovenous shunt-induced thrombosis were 0.6 micromol/kg/h for SF303, 0.035 micromol/kg/h for SK549, 0.01 micromol/kg/h for recombinant tick anticoagulant peptide, 0.4 micromol/kg/h for DX-9065a, 21 U/kg/h for heparin, and 23 U/kg/h for low molecular weight heparin. SK549 produced a concentration-dependent antithrombotic effect with an IC(50) of 0.062 microM. To evaluate its potential oral efficacy, SK549 was given intraduodenally at a dose of 5 mg/kg; it produced a peak antithrombotic effect of 59 +/- 4% with a duration of action greater than 6.7 h. Therefore, our study suggests that SF303, SK549, and their analogs represent a new class of synthetic fXa inhibitors that may be clinically useful as antithrombotic agents.

Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2.

Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for thrombin activation. Herein we report a series of isoxazoline derivatives which are potent FXa inhibitors. Optimization of the side chain at the quaternary position of the isoxazoline ring led to SK549 which showed subnanomolar FXa potency (K(i) 0.52 nM). SK549 shows good selectivity for FXa compared to thrombin and trypsin, potent antithrombotic effect in the rabbit arterio-venous thrombosis model, and improved pharmacokinetics relative to other compounds evaluated from this series.

Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1.

Thrombosis is a major cause of mortality in the industrialized world. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for prothrombin activation. We report a series of novel biaryl-substituted isoxazoline derivatives in which the biaryl moiety was designed to interact with the S(4) aryl-binding domain of the FXa active site. Several of the compounds herein have low nanomolar affinity for FXa, have good in vitro selectivity for FXa, and show potent antithrombotic efficacy in vivo. The three most potent compounds (33, 35, and 37) have inhibition constants for human FXa of 3.9, 2.3, and 0.83 nM, respectively, and ID(50)'s ranging from 0.15 to 0.26 micromol/kg/h in the rabbit arterio-venous thrombosis model.

Pyrazoles, 1,2,4-triazoles, and tetrazoles as surrogates for cis-amide bonds in boronate ester thrombin inhibitors.

Substituted pyrazoles, 1,2,4-triazoles, and tetrazoles are good surrogates for cis-amide bonds in a series of boronate ester thrombin inhibitors.

Pharmacology of XR510, a potent orally active nonpeptide angiotensin II AT1 receptor antagonist with high affinity for the AT2 receptor subtype.

The angiotensin II (Ang II) type 1 receptor (AT1) mediates all known physiological effects of ANG II, whereas functions of the type 2 (AT2) receptor are not clear. Should undesirable AT2 effects be identified, it may be advantageous to combine antagonism of AT1 and AT2 receptors. XR510 was shown to inhibit the specific binding of [125I]Sar1,Ile8-Ang II for AT1 and AT2 subtype binding sites in rat adrenal membranes with IC50 of 0.26 and 0.28 nM, respectively, and in human tissues with subnanomolar binding affinity. In isolated rabbit aorta, XR510 exerted insurmountable Ang II antagonism with a Kb value of 4 nM. In conscious renal hypertensive rats, XR510 decreased blood pressure (BP) with intravenous (i.v.) and oral (p.o.) ED30 of 0.08 and 0.27 mg/kg, respectively. In spontaneously hypertensive rats (SHR), repeated daily oral dosing of XR510, losartan, and enalapril at 30 mg/kg/day decreased BP similarly. In conscious furosemide-treated dogs, XR510, given either intravenously or orally, decreased BP. These results suggest that XR510 is an orally active and selective Ang II receptor antagonist with equal binding affinities for AT1 and AT2 receptor binding sites.