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MEDI 434 Computational investigation of direct antitumor cell activity of novel bisphosphonates Michael P. Hudock1, Yonghui Zhang2, Kilannin Krysiak2, Fenglin Yin3, Rong Cao4, Yongcheng Song2, Ermond van Beek5, Socrates Papapoulos5, and Eric Oldfield2. 1 ; Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, 607 S. Mathews Avenue, Urbana, IL 61801, hudock uiuc , 2 ; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, 3 ; Center for Biophysics and Computational Biology, University of Illinois at Urbana Champaign, Urbana, IL 61801, 4 ; Center for biophysics and computational biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, 5 ; Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden NA, Netherlands We report here a computational investigation of the direct effects of several novel classes of bisphosphonates in three tumor cell lines. For several such compounds, we have observed very low micro-molar anti-tumor cell activity and reduced bone affinity. The compounds were designed and synthesized in our laboratory and screened against breast adenocarcinoma MCF-7 ; , CNS glioblastoma SF-268 ; and lung large cell NCI-H460 ; . In order to probe the mechanism of action of these compounds, we also performed enzyme screening against farnesyl diphosphate synthase FPPS ; , a known target of other nitrogen containing bisphosphonates, and other enzymes in the mevalonate pathway. 3D-QSAR CoMSIA analysis of these compounds suggests the importance of hydrophobic features typical in our most potent species, and additional modeling suggests the possibility of multiple targets for these compounds. These results suggest that this new class of bisphosphonates could be used in future cancer therapies. MEDI 435 Synthesis and profiling of a new multiple kinase inhibitor chemotype Anne-Marie Egert1, Simone Kohfeld1, Frank Totzke2, Christoph Schchtele2, Michael H. G. Kubbutat2, Daniel W. Zaharevitz3, and Conrad Kunick1. 1 ; Institut fr Pharmazeutische Chemie, Technische Universitt Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany, Fax: + 49- 0 ; 531-391-2799, c.kunick tu-bs , 2 ; ProQinase GmbH, 79106 Freiburg, Germany, 3 ; Information Technology Branch, Developmental Therapeutics Program, National Cancer Institute, Bethesda, MD 20892 Hyperactivity of kinases is involved in manifold tumor diseases and therefore the use of kinase inhibitors is an established option for cancer treatment. Recently, several drugs have been launched inhibiting simultaneously more than one cancer related kinase, e. g. sorafenib, sunitinib and dasatinib. By combining privileged heterocyclic scaffolds found in other kinase inhibitors we have designed a new multiple kinase inhibitor chemotype, 2-anilino-5, 7-dihydro6H-pyrimido[5, 4-d][1]benzazepin-6-one. Members of this new compound class exhibit antiproliferative activity in vitro when incubated with cancer cell lines. Synthesis and profiling of the new inhibitors both in an array of cancer related kinases and in the in vitro cell line screening of the National Cancer Institute will be presented in the poster. Su bstan ce ab use-wheth er it is the abu se of prescrip tion medication s, illicit drug s su ch caine, "seas on s pliff" an d marijuana o r alcoh ol-can have destru ctiv e effects o n the ab user. Su bstan ce abu se o ften leads to ad diction. T his is generally characterized by an uncon trollable crav ing fo r th subs tance, the in ab ility to s top u sin g the sub stan ce, th e ap pearan ce of withdrawal sy mp toms and the need fo r increasin g amounts o f the s ubs tance and omnicef.

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Fering selectivity to bind with mutually competitive affinities to cAMP and cGMP KM 0.2 and 0.3 M, respectively ; Degerman et al., 1997; Perry and Higgs, 1998 ; . PDE3 isoforms are particularly distributed within heart, lung, liver, platelets, immunocytes, and adipose tissues Perry and Higgs, 1998 ; . PDE3, furthermore, is known for its cGMPinhibited characteristics because some biological effects of endogenous cGMP may be mediated by inhibition of PDE3, which results in increased cAMP and activation of cAMPdependent protein kinase Degerman et al., 1997 ; . Amrinone is one of the selective inhibitors of PDE3 and a plethora of other selective inhibitors have been already identified Degerman et al., 1997; Perry and Higgs, 1998 ; . Selective inhibition of PDE3 emerged with similar behavior to the effect of 8-methoxymethyl-IBMX, despite the observation that amrinone at 100 M partially reduced LPS-mediated secretion of TNF- , with strong inhibitory mechanics on IL-6 biosynthesis. This effect bears an interesting therapeutic approach, because type 3 PDEs have been reported to be active in the airway epithelium Kelley et al., 1995 ; , consistent with the notion that selective PDE3 blockade interfered with the progression of cystic fibrosis in vivo Al-Nakkash and Hwang, 1999; Smith et al., 1999 ; , reduced ischemiareperfusion injury in the heart Rechtman et al., 2000 ; , and conferred cardiac protection under surgery Butterworth et al., 1995 ; . PDE4 isoforms are cAMP-specific KM 4 M ; and cGMPinsensitive KM 3000 M ; phosphodiesterases, distributed in Sertoli cells, kidney, brain, liver, lung, and immunocytes Essayan, 1999 ; . There are four PDE4 genes encoding distinct isoforms A, B, C, and D ; with additional diversity particularly arising from alternative initiation sites and or alternative splicing Perry and Higgs, 1998 ; . The immunopharmacological potential of rolipram, a selective inhibitor of PDE4, is well documented. For instance, it was reported that, from a functional standpoint, the up-regulation of PDE4 activity resulted in a heterologous desensitization to the actions of prostaglandin E2 and, presumably, other adenylyl cyclase activators, thereby conceivably concluding that this regulatory pathway could compromise the long-term antiasthmatic efficacy of -adrenoreceptor agonists Torphy et al., 1995 ; . Furthermore, it has been recently reported that the second-generation PDE4 inhibitor Ariflo, SB-207499 ; has antiasthmatic activity in vivo Underwood et al., 1998 ; and an anti-inflammatory potential in vitro Barnette et al., 1998 ; , indicating a therapeutic potential for the treatment of asthma and other allergic inflammatory disorders. Of note, subtype selective inhibition of PDE4 has been shown to suppress human inflammatory cell function Manning et al., 1999 ; , inflammatory hyperalgesia Cunha et al., 1999 ; , and immunological inflammation Boichot et al., 2000; Ehinger et al., 2000 ; . Our results jive with the anti-inflammatory potential assigned to PDE4 inhibition, consistent with the observations reported that rolipram Semmler et al., 1993; Kasyapa et al., 1999 ; , ariflo Griswold et al., 1998 ; , and RPR-73401 Brideau et al., 1999 ; regulate mediator-effected biosynthesis of TNF- , leukotrienes, and other interleukins. The observation, however, that rolipram exhibited a dual response on LPS-mediated TNF- production remains of particular interest in the alveolar epithelium, indicating dosedependent specificity and cytokine selectivity IL-6 versus TNF and cefepime. Growing trend. In the 1980s, abbreviated new drug applications ANDAs ; containing paragraph IV certifications i.e., patent challenges ; were a rarity. In the 1990s, the share increased to 12%, and by 2000, it had increased to 20%. Since then, the percentage has increased dramatically. While the Indian pharma companies have not been as visible in paragraph IV wins, the number of their filings has increased as well, for example, . Was greater in those with atrial fibrillation. 15% had atrial fibrillation with the highest frequency in elderly patients. A total of 27 4.4% ; cerebrovascular events occurred, 13% in those having atrial fibrillation and 3% in those with sinus rhythm. Advanced age rather than the presence of atrial fibrillation was the important risk factor for embolism. From this study the indication for prophylactic anticoagulation is doubtful in hyperthyroid patients with atrial fibrillation30. In younger patients with hyperthyroidism and atrial fibrillation who do not have other heart disease, hypertension or other risk factors for embolism, the risk of anticoagulant therapy probably outweighs the benefit31. The risk of embolism in thyrotoxic atrial fibrillation exceeds that of lone atrial fibrillation. The majority of clinically evident emboli in patients with hyperthyroidism and atrial fibrillation involves central nervous system and occur early in the course of the disease32. Elderly patients with thyrotoxicosis and atrial fibrillation and those with other risk factors for thromboembolism have significantly increased risk for arterial thromboembolism and anticoagulant treatment is indicated. Elderly patients are particularly at risk for hemorrhagic complications and hence close monitoring of prothrombin time is required in elderly patients on warfarin. Antiplatelet agents like aspirin may afford some protection against cardioembolic stroke in patients with atrial fibrillation, although these are more effectively prevented by anticoagulation33. Treatment Mainstay of treatment in patients with atrial fibrillation and hyperthyroidism is restoration of euthyroid status. This is by use of antithyroid drugs like carbimazole, propyl thiouracil or radio-iodine . Surgery of thyroid gland is done after achieving euthyroid status by drugs. Beta blockers like propranalol or atenolol are useful in thyrotoxic atrial fibrillation to reduce heart rate and cardiac failure34, 35. Restoration of euthyroid status is frequently associated with conversion to sinus rhythm . In a study of 163 patients with thyrotoxicosis and atrial fibrillation, 62% were in sinus rhythm within 8-10 weeks after achieving euthyroid state36. After 3 months only few will revert spontaneously to sinus rhythm. Electrical or pharmacologic cardioversion may be attempted in patients remaining in atrial fibrillation after achieving euthyroid status. Rate of reversion to sinus rhythm is less in older patients and in those with longer duration of atrial fibrillation and structural heart disease. In another study, of the 256 patients who underwent surgery for thyrotoxicosis 23% had preoperative atrial fibrillation. After surgery 47% of them reverted to sinus rhythm and the rest had better responsiveness to antiarrhythmic drugs. Restoration of sinus rhythm occurred mostly in patients younger than 50 years while in older patients atrial fibrillation persisted37. Treatment of subclinical hyperthyroidism is controversial . Some authors advocate careful follow up of these patients for development of overt hypothyroidism, cardiac dysrhythmias and other circulatory complications38. But others have suggested routine treatment for subclinical hyperthyroidism as it is associated with adverse cardiac events. Antithyroid drugs or radio-iodine may be useful especially in those with nodular goiter and cardiac risk factors39. Treatment of subclinical hyperthyroidism with antithyroid drugs was shown to reduce left ventricular mass index, heart rate, atrial and ventricular premature beats and atrial fibrillation. Many patients in this group with subclinical hyperthyroidism had symptoms, high Wayne clinical index and echocardiographic abnormalities which reduced with treatment40. Biondi et al observed that treatment with selective beta1 blocker bisoprolol reduces left ventricular mass index and atrial arrhythmias in patients taking long term thyrotropin suppressive therapy with thyroxine41. Dosage of thyroxine in patients receiving replacement therapy should be adjusted to a normal and not suppressed thyrotropin level42. Conclusion Atrial fibrillation is a major cause of morbidity and mortality in overt as well as Indian Pacing and Electrophysiology Journal ISSN 0972-6292 ; , 5 4 ; : 305-311 2005 and cefixime. The Controlled Substances Act cannot bear a medical necessity defense to distributions of marijuana, we do not find guidance in this avoidance principle.89 [Emphasis added], because action of carbimazole.

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