Division of Medicinal Chemistry Abstracts-235th ACS National ...

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life of 52 min and the tumor uptake was significantly higher (1.8 ± 0.7%ID/g).We prepared radiochemically pure, Tc-99m-labeled chlorotoxin, multimerization of chlrotoxin resulted in enhanced affinity for cancer cell lines. The high uptake by tumor makes this trimeric chlorotoxin as the favorable ligand for tumor targeting in vivo. MEDI 15 Multidentate small molecule inhibitors of VHR phosphatase: A new drug target for the treatment of cervical cancer Lutz Tautz 1 , Ana V. Miletic 1 , Shuangding Wu 1 , Fabio Cerigno 1 , Yutaka Arimura 1 , Torkel Vang 1 , Jesus Vazquez 1 , Scott Williams 1 , Rachel Henkens 2 , Tikva Hayes 1 , Stefan Vasile 3 , Souad Rahmouni 2 , Maurizio Pellecchia 1 , and Tomas Mustelin 1 . (1) Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research, 10901 N Torrey Pines Rd, La Jolla, CA 92037, tautz@burnham.org, (2) Liège University, Liège, Belgium, (3) High Throughput Screening Center, Burnham Institute for Medical Research, La Jolla, CA 92037 VHR is a dual-specific phosphatase and a negative regulator of the Erk and Jnk mitogenactivated protein kinase pathways. Loss of VHR causes cell cycle arrest in HeLa cervix carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. Moreover, VHR was found to be upregulated in several cervix cancer cell lines as well as in squamous intraepithelial lesions and squamous cell carcinomas of the uterine cervix. Here we report the development of novel multidentate small molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations in vitro and hold the growth of cancer cells at low micromolar concentrations. High throughput chemical library screening was used to identify hits, and structure-based methods were applied in the search for analogs with improved potency and selectivity, resulting in multidentate inhibitors. The binding mode of these novel compounds was confirmed by X-ray crystallography. MEDI 16 Discovery of 2-acylindoles as potent, orally active human glucagon receptor antagonists Christopher J. Sinz 1 , Amy Bittner 1 , Ronald M. Kim 1 , Ed Brady 2 , Mari Rios Candelore 3 , Victor D- H. Ding 3 , Guoquiang Jiang 3 , Zhen Lin 1 , Ashley Rouse Lins 1 , Peggy McCann 2 , Corin Miller 4 , Kiyean Nam 5 , Sajjad A. Qureshi 3 , Gino Salituro 1 , Richard Saperstein 2 , Jackie Shang 6 , Deborah Szalkowski 3 , Laurie Tota 3 , Michael Wright 3 , Regina Wang 6 , Shiyao Xu 6 , Xiaodong Yang 3 , Bei Zhang 3 , Milton Hammond 1 , James Tata 1 , and Emma Parmee 1 . (1) Department of Medicinal Chemistry, Merck and Co., Inc, P.O. Box 2000, RY800-C303, Rahway, NJ 07065, Fax: 732- 594-9473, christopher_sinz@merck.com, (2) Department of Pharmacology, Merck and Co., Inc, Rahway, NJ 07065, (3) Metabolic Disorders - Molecular Endocrinology, Merck & Company, Inc, Rahway, NJ 07065, (4) Research Imaging, Merck & Company, Inc, Rahway, NJ 07065, (5) Molecular Systems, Merck & Co., Inc, Rahway, NJ 07065, (6) Department of Drug Metabolism, Merck and Co., Inc, Rahway, NJ 07065 Glucagon and insulin are the primary counter-regulatory hormones responsible for glucose homeostasis. Glucagon is secreted from pancreatic alpha-cells in response to falling plasma glucose levels. Activation of the glucagon receptor, a G-protein coupled receptor located
predominately in the liver, leads to increased hepatic glucose production via glycogenolysis and gluconeogenesis. In patients with type 2 diabetes, excessive hepatic glucose production is a key contributing factor to hyperglycemia. Thus, glucagon receptor antagonists have attracted significant interest as a novel treatment for type 2 diabetes. We found that N-alkyl-2-acylindoles such as compound 1 are potent glucagon receptor antagonists; however, these compounds show poor activity in vivo due to rapid metabolic turnover. Improved metabolic stability was realized by substitution of the indole nitrogen with an aryl group. Further optimization led to compound 2, a potent and selective human glucagon receptor antagonist that displays good efficacy in rodent diabetes models and favorable pharmacokinetic properties in preclinical species. MEDI 17 Synthesis and QSAR studies of CADA analogs wth CD4 down-modulating and anti-HIV activities Thomas W. Bell, Department of Chemistry, University of Nevada, Reno, NV 89557-0216, Fax: 775-784-6804, twb@unr.edu HIV attachment via the CD4 receptor is an important target for developing novel approaches to HIV chemotherapy. Cyclotriazadisulfonamide (CADA) is a 1,5,9-triazacyclododecane that inhibits HIV at submicromolar levels by specifically down-modulating cell-surface and intracellular CD4. An effective 5-step synthesis of CADA has been modified to produce may analogs. Tail-group analogs have been made by removing the benzyl tail of CADA and replacing it with various alkyl, acyl, alkoxycarbonyl and aminocarbonyl substituents. A series of side-arm analogs has also been prepared by modifying the CADA synthesis, replacing the toluenesulfonyl side arms with other sulfonyl groups. Testing of these compounds in MT 4 cells shows a wide range of CD4 down-modulation potency, which correlates with ability to inhibit HIV-1. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were constructed , based on the X-ray crystal structures of four compounds, including CADA. Both models indicate that steric bulk of the tail group and, to a lesser extent, the side arms mainly determine CD4 down-modulation potency in this series of compounds.
Page 1 and 2: Division of Medicinal Chemistry Abs
Page 3 and 4: discovery of S/GSK364735 was a resu
Page 5 and 6: compounds was then performed target
Page 7: MEDI 13 Potent, brain-penetrant, hy
Page 11 and 12: Candidate Optimization Department,
Page 13 and 14: acceptor atoms as the core componen
Page 15 and 16: Prostaglandin (PG) D 2 is an allerg
Page 17 and 18: polymerization, as described, by pr
Page 19 and 20: MEDI 34 Pyrogallol and its analogs
Page 21 and 22: Nicos A. Petasis 1 , Jasim Uddin 1
Page 23 and 24: Yong-Gil Kim, Joon Heo, Mi-Kyung Ji
Page 25 and 26: A new class of potent NK1 receptor
Page 27 and 28: The significant antiviral propertie
Page 29 and 30: Laboratories, West Point, PA 19486,
Page 31 and 32: MEDI 58 Preparation and antiviral a
Page 33 and 34: MEDI 62 Caco-2 cell based assay dev
Page 35 and 36: FMS-like tyrosine kinase 3 (FLT3) r
Page 37 and 38: MEDI 70 Synthesis of bisphosphonate
Page 39 and 40: ing. These observations suggest a p
Page 41 and 42: MEDI 77 Probing the structure-activ
Page 43 and 44: B-Raf kinase plays a critical role
Page 45 and 46: Gal-CS was used to prepare nanopart
Page 47 and 48: MEDI 88 Trifluoromethyl substituted
Page 49 and 50: MEDI 92 Discovery of novel small mo
Page 51 and 52: MEDI 96 Synthesis and antiprolifera
Page 53 and 54: MEDI 99 Development of novel antica
Page 55 and 56: MEDI 103 Discovery of N-aryl-9-oxo-
Page 57 and 58: Compounds that interfere with micro
Page 59 and 60:
Carbonyl reductase (CR) has been im
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Apoptosis is a process of cell deat
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MEDI 120 Novel purine based "atypic
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MEDI 124 Efficient removal of ruthe
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library approach using technology-e
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MEDI 131 Synthesis and biological e
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MEDI 135 Identification of AT-1002
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Spectroscopic evidence was used to
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MEDI 142 Molecular basis for irreve
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MEDI 146 Effect of fluorine on subs
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MEDI 151 Overview of newer approach
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MEDI 156 Defining structure-activit
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MEDI 160 Bivalent inhibitors of P-g
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MEDI 164 Molecular basis for effica
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MEDI 167 Discovery of the highly po
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highly asymmetric, closely packed d
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4/WP14-3, Sumneytown Pike, West Poi
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MEDI 179 Design, synthesis, and eva
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MEDI 182 Substituted-pyrrole 2-amin
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MEDI 186 Discovery and optimization
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phosphatase SHIP. Bioassay guided f
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epibatidine for nicotinic channels.
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derivative with striking solubility
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MEDI 203 Core-modified mannopeptimy
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MEDI 207 Enhancing the kinetic prof
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hydroxyphenyl)piperazin-1-yl)butyl)
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migration of people from these area
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Schistosomiasis is, after malaria,
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-Ketoacyl-ACP-synthase III (FabH) h
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MEDI 225 Synthesis of the analog of
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MEDI 229 Structure-based virtual sc
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MEDI 234 TG100801: A prodrug for th
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In the past, large collections of c
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approach to the treatment of autoim
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logPe values. The residual mean squ
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Oligo-chitosan (OCS) which is a kin
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characterization of novel muscarini
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MEDI 257 Rigid analogs of 4,4-diary
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MEDI 261 Strategies toward improvin
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disease. It is generally accepted t
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(BBB). Our preliminary in vitro dat
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It is well-documented that androgen
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MEDI 276 Investigating the manipula
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were screened by FACS sarin labeled
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MEDI 285 Design, synthesis and biol
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equipment set-up and large scale ma
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Significant effort has been directe
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esearch was supported by funds from
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synthesized a series of carbamoylch
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proceeded more rapidly by switching
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genes. With the understanding of th
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MEDI 310 Optimized methods for the
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Coupled with crystallographic data,
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MEDI 317 Design and synthesis of hy
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MEDI 320 Synthesis and antibacteria
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DTPA. Incorporation of the nitro fu
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MEDI 328 The mechanism of bioreduct
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esistance, there is an urgent need
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Giving the Rule-of-5 a more accurat
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MEDI 338 Structure guided design of
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MEDI 342 Synthesis of peptide-amilo
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MEDI 346 Design, synthesis, and ant
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