Urinary estrogen metabolites and long-term mortality following breast cancer

Background: Estrogen metabolite concentrations of 2-hydroxyestrone (2-OHE1) and 16-hydroxyestrone (16-OHE1) may be associated with breast carcinogenesis. However, no study has investigated their possible impact on mortality after breast cancer. Methods: This population-based study was initiated in 1996–1997 with spot urine samples obtained shortly after diagnosis (mean ¼ 96 days) from 683 women newly diagnosed with first primary breast cancer and 434 age-matched women without breast cancer. We measured urinary concentrations of 2-OHE1 and 16-OHE1 using an enzyme-linked immunoassay. Vital status was determined via the National Death Index (n ¼ 244 deaths after a median of 17.7 years of follow-up). We used multivariable-adjusted Cox proportional hazards to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the estrogen metabolites-mortality association. We evaluated effect modification using likelihood ratio tests. All statistical tests were two-sided. Results: Urinary concentrations of the 2-OHE1 to 16-OHE1 ratio (>median of 1.8 vs <median) were inversely associated with all-cause mortality (HR ¼ 0.74, 95% CI ¼ 0.56 to 0.98) among women with breast cancer. Reduced hazard was also observed for breast cancer mortality (HR ¼ 0.73, 95% CI ¼ 0.45 to 1.17) and cardiovascular diseases mortality (HR ¼ 0.76, 95% CI ¼ 0.47 to 1.23), although the 95% confidence intervals included the null. Similar findings were also observed for women without breast cancer. The association with all-cause mortality was more pronounced among breast cancer participants who began chemotherapy before urine collection (n ¼ 118, HR ¼ 0.42, 95% CI ¼ 0.22 to 0.81) than among those who had not (n ¼ 559, HR ¼ 0.98, 95% CI ¼ 0.72 to 1.34; Pinteraction ¼ .008). Conclusions: The urinary 2-OHE1 to 16-OHE1 ratio may be inversely associated with long-term all-cause mortality, which may depend on cancer treatment status at the time of urine collection

Pharmaceutically active compounds and methods for use

New fused thiophene compounds are provided and methods of using those conmpounds for a variety of therapeutic indications. Compounds of the invention are particulary useful for treatment of neuropathic pai

Allosteric modulators of the A1 adenosine receptor

Title compd. I [R1 = H, (un)substituted alkyl, aryl or cycloalkyl; R2, R3 and R4 independently = H, halo, OH, NO2, CN, (un)substituted alkyl, aryl, cycloalkyl or alkoxy; Q = (un)substituted piperidinyl, azepinyl, 5-membered spirocyclic ring, etc.], and their pharmaceutically acceptable salts, are prepd. and disclosed as allosteric modulators of the A1 adenosine receptor and, thus, may be employed for the treatment of conditions mediated by the A1 adenosine receptor. E.g., II was prepd. and demonstrated an IC50 value of about 100 nM in a functional assay measuring the cAMP level in CHO cells expressing the human A1-adenosine receptor. As allosteric modulators of the A1 adenosine receptor, I should be prove useful for treatment of pain, in particular, chronic pain such as neuropathic pain; cardiac disease or disorder such as cardiac disarrhythmias, e.g., peroxysmal supraventricular tachycardia, angina, myocardial infarction and stroke; neurol. disease or injury; sleep disorder; epilepsy; and depression

Preparation of substituted purinylpyrazolylacetamides as adenosine A2B receptor antagonists.

The title compds. I [R1, R2 = (un)substituted alkyl; R3 = H, halo; R4, R5 = H or alkyl; R6 = (un)substituted (hetero)aryl] which are adenosine A2B receptor antagonists and, thus, may be employed for the treatment of conditions and diseases mediated by the adenosine A2B receptor activity, were prepd. Such conditions and diseases include, but are not limited to, chronic and acute inflammatory diseases involving degranulation of mast cells, e.g., asthma, allergic rhinitis and allergic dermatitis; impaired sensitivity to insulin, e.g., type 2 diabetes, non-insulin dependent diabetes, pre-diabetic state, and impaired glucose tolerance; diseases in which angiogenesis is a key component of pathogenesis, e.g., solid tumors and angiogenic retinopathies; apnea of preterm infants; myocardial reperfusion injury; inflammatory bowel disease; autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and lupus erythematosus; diseases involving microvascular abnormalities of the retina that are mediated by adenosine A2B receptors, e.g., retinopathy of prematurity, macular degeneration, and diabetic retinopathy; and cardiac diseases including hyperplasia consequent to hypertension, arteriosclerosis, and heart attack. E.g., a multi-step synthesis of II, starting from aniline, was described. Exemplified compds. I were tested in adenosine A2B receptor binding and functional assays (data given). Pharmaceutical compn. comprising the compd. I is disclosed

ALLOSTERIC MODULATORS FOR THE A1 ADENOSINE RECEPTOR

A review. Allosteric modulators of endogenous adenosine represent an alternative to direct acting adenosine agonists and nucleoside uptake blockers. These compds. can selectively enhance the response to adenosine in only those organs or localized areas of a given organ in which prodn. of adenosine is increased. The present article is an overview of the recent patent literature related to allosteric modulators of adenosine function on the A1 receptor. In particular, the compds. with improved potency as enhancers and reduced antagonist properties are mentioned. Among the reported compds., two mols. appear to be of potential therapeutic utility. A synergistic combination of PD-81723 and cyclopentyladenosine, an allosteric enhancer and agonist, resp., of the adenosine A1 receptor, appeared to be effective to induce angiogenesis. Moreover, (2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-(4-chloro-phenyl)methanone appears to be active for the treatment of neuropathic pain without co-administration of adenosine

Synthesis of 2-amino-3-heteroaroylthiophenes and evaluation of their activity as potential allosteric enhancers at the human A(1) receptor

2-Amino-3-benzoylthiophenes are allosteric enhancers of agonist binding to the adenosine A1 receptor. New compds. bearing an heteroaroyl instead of the benzoyl moiety at the 3-position of the thiophene were synthesized. The Ph ring was replaced with heterocycles that possess heteroatoms able to form hydrogen bonds (2-furanyl, 2-benzofuranyl, 2-pyridinyl) or with a thienyl moiety as isostere of the Ph ring (2-thienyl, 3-thienyl and 5-halo-2-thienyl). The effect of several alkyl substituents at positions 4 and 5 of the thiophene ring to increase enhancer activity was detd. The ability of the new mols. to reduce the cAMP content in CHO cells expressing the human adenosine A1 receptor was evaluated. Compds. with hydrogen bond-forming heteroatoms did not show significant activity as allosteric enhancers. On the other hand, compds. with an unsubstituted thienyl moiety as replacement for the Ph ring were nearly as efficacious as PD 81,723, the prototypical A1 allosteric enhancer. Alkyl substituents at positions 4 and 5 of the thiophene ring were tolerated while a substituted piperidine ring was not tolerated. It was concluded that hydrogen bonds could not be formed in the domain of the receptor that accommodates the Ph ring of 2-amino-3-benzoylthiophene derivs., indicating that this domain is hydrophobic

Synthesis and biological characterization of [H-3] (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-chlorophenyl)-methan one, the first radiolabelled adenosine A(1) allosteric enhancer

Among the adenosine A1 allosteric enhancers reported so far, compd. (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-chlorophenyl)methanone (I, named T-62) has shown biol. properties similar to those of PD 81,723, the ref. A1 allosteric enhancer and it has been more fully pharmacol. investigated. The prepn. of the radiolabeled form of compd. I and its characterization by satn. binding expts. are reported. These studies allowed us to demonstrate for the first time the existence of a specific, allosteric site on the A1 receptor

Pyrrolo- and pyrazolo-[3,4-e][1,2,4]triazolo[1,5-c]pyrimidines as adenosine receptor antagonists

The discovery and development of adenosine receptor antagonists have represented for years an attractive field of research from the perspective of identifying new drugs for the treatment of widespread disorders such as inflammation, asthma and Parkinson's disease. The present work can be considered as an extension of our structure-activity relationship studies on the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) nucleus, extensively investigated by us as a useful template, in particular, for the identification of A2A and A3 adenosine receptor antagonists. In order to explore the role of the nitrogen at the 7-position, we performed a new synthetic strategy for the prepn. of pyrrolo[3,4-e][1,2,4]triazolo[1,5-c]pyrimidine derivs. which can be considered as 7-deaza analogs of the parent PTPs. We also synthesized a novel series of pyrazolo[3,4-e][1,2,4]triazolo[1,5-c]pyrimidines as junction isomers of the ref. compds. In both cases we obtained some examples of potent antagonists (K i in the low nanomolar range) with variable selectivity profiles in relation to the nature of substituents introduced at the C 5-, N 8- and/or N 9-positions. The pyrrolo-triazolo-pyrimidine deriv. 9b (I) appeared to be a potent A3 adenosine receptor antagonist (K i = 10 nM) with good selectivity over hA1 (74-fold) and hA2A (20-fold) adenosine receptors combined with low activity at the hA2B subtype (IC50 = 906 nM). Moreover, some examples of high-affinity A1/A2A dual antagonists have been identified in both series. This work constitutes a new and important contribution for the comprehension of the interaction between PTPs and adenosine receptors