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

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MEDI 21 Discovery of a second generation FBPase inhibitor, MB07803, with reduced metabolism and improved oral bioavailability Qun Dang 1 , Paul D. van Poelje 2 , Robert H Lemus 1 , Feng Tian 1 , Haiqing Li 1 , Scott C Potter 2 , James Fujitaki 2 , David Linemeyer 2 , and Mark D. Erion 3 . (1) Department of Chemistry, Metabasis Therapeutics, Inc, 11119 North Torrey Pines Road, La Jolla, CA 92037, dang@mbasis.com, (2) Department of Biosciences, Metabasis Therapeutics, Inc, La Jolla, CA 92037, (3) Research & Development, Metabasis Therapeutics Inc, La Jolla, CA 92037 MB06322 (CS-917, a prodrug of FBPase inhibitor MB05032) significantly lowered fasting plasma glucose levels in patients with type 2 diabetes (T2DM) during two phase 2a clinical trials. The second generation program sought to improve oral bioavailability and eliminate the formation of an N-acetyl metabolite of MB05032. Modification of the electronic character of the thiazole FBPase inhibitor series led to a potent human N-acetyltransferase-resistant lead, MB07729 (IC50 = 21 nM; 0% N-acetylation by NAT1 and NAT2). Prodrug optimization resulted in phosphonic diamide MB07803, which demonstrated good oral bioavailability in rats (30-40%) and monkeys (50-60%), and efficient conversion to MB07729. MB07803 elicited marked glucose-lowering effects in rodent models of T2DM (e.g. db/db mice and ZDF rats, MED of 10- 30 mg/kg) and in normal fasted monkeys (MED = 3 mg/kg). In a phase 1 clinical trial, MB07803 was well tolerated and led to dose-linear exposure of MB07729, with minimal formation of the N- acetyl metabolite. MEDI 22 From virtual screening to clinic: Discovery of Cevoglitazar T. R. Vedananda 1 , Mike Sabio 2 , James Stanton 3 , Hollis Tomaselli 2 , James Fraser 4 , Goli Naderi 2 , Jenny Tan 2 , Travis Stams 5 , Brian Boettcher 3 , Barbara Fanelli 2 , Jianping Gao 6 , Richard Deacon 3 , Shari Caplan 3 , Ping Chen 3 , Beatriz Dardik 3 , and Ricardo Chatelain 3 . (1) Global Discovery Chemistry and Department of Diabetes and Metabolism, Novartis Institute for Biomedical Research Inc, Cambridge, MA 02139, (2) (3) Department of Diabetes and Metabolism, (4) Global Discovery Chemistry and Department of Diabetes and Metabolism, (5) Protein Stucture Biology, (6) School of Physics, Georgia Institute of Technology, Atlanta, GA 30332-0430 Despite the availability of several classes of anti-diabetic agents, significant medical need remains due to limited impact of therapies on disease progression, restricted application of existing agents and a lack of pathophysiological impact. Peroxisome proliferators activated receptor (PPAR) alpha and gamma dual agonists are expected to improve glycemic control, insulin resistance and the metabolic syndrome as a consequence of their combined anti-diabetic and anti-dyslipidemic properties. The discovery of Cevoglitazar as a potent PPAR alpha/gamma dual agonist was a combined effort of virtual screening of 3D databases and structure-based drug design. Computer aided molecular design was initiated by examining known ligand bound PPAR gamma X-ray structures. To develop a pharmacophore model for database searching, observed protein-ligand interactions were simplified to an essential set of three hydrogen bonds, identifying three
acceptor atoms as the core components of the pharmacophore model. Using Unity module of Sybyl, searches were performed on internal and external 3D databases covering nearly 1.3 million structures. All 4021 hits were visually inspected and those which could not be transformed into potential synthetic targets were eliminated. For the surviving hits, structural modifications were facilitated by docking calculations. Subsequent structure-based elaboration of most advanced leads led to the identification of Cevoglitazar as a potent PPAR alpha/gamma dual agonist. Herein we wish to disclose for the first time, the discovery of Cevoglitazar, a potent PPAR alpha/gamma dual agonist advanced into clinical development. MEDI 23 Design and synthesis of quinazoline derivatives as novel, potent multiacting HDAC and receptor tyrosine kinase inhibitors for the treatment of cancer Xiong Cai, Hai-Xiao Zhai, Cheng-June Lai, Rudi Bao, and Changgeng Qian, Medicinal Chemistry, Curis Inc, 45 Moulton Street, Cambridge, MA 02138, xcai@curis.com HDACs and receptor tyrosine kinases (RTK) such as EGFR and Her2 are validated cancer targets. A multi-targeted HDAC and RTK inhibitor may offer more therapeutic benefits in cancer compared to single acting agents due to potential synergistic effects between HDAC and RTK inhibition. By incorporating HDAC inhibitory functionality into the RTK inhibitor pharmacophore, we designed and synthesized a novel quinazoline series of potent multi acting compounds. The synthesis and SAR surrounding this class of compounds will be discussed. CUDC-101 is one of the lead molecules in the series. In vitro, CUDC-101 displays potent inhibitory activity as well as anti-proliferation and apoptosis-inducing activities against a broad range of cancer cell types with equal or greater potency than SAHA (an HDAC inhibitor), erlotinib (an EGFR inhibitor) and lapatinib (an EGFR/Her2 kinase inhibitor) or combinations thereof. In vivo, CUDC-101 targets all three pathways and is effective against various cancer models. CUDC-101 also displays a favorable safety profile. These results suggest that CUDC-101 may represent a novel treatment option in cancer and a suitable candidate for clinical development. MEDI 24 Macrocyclic peptidyl biaryl-ether inhibitors provide evidence for the catalytic versatility of the 20S proteasome Marion G. Götz 1 , Michael Groll 2 , Markus Kaiser 3 , Elisabeth Weyher 3 , and Luis Moroder 3 . (1) Department of Chemistry, Whitman College, 345 Boyer Ave, Walla Walla, WA 99362, gotzmg@whitman.edu, (2) Charité, Berlin, Germany, (3) Max-Planck-Institute for Biochemistry, Martinsried, Germany The 20S proteasome (core particle) forms together with the 19S regulatory cap the multicatalytic 26S proteasome. The core particle exhibits three different specific activities, a caspase-like, a trypsin-like and a chymotrypsin-like activity, which are controlled by the β1, β2, and β5 subsites. The potent natural product inhibitor TMC-95A (1) is a macrocyclic tripeptide derivative, which inhibits the active site by a non-covalent hydrogen bonding array. Previously, a simplified TMC-
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Page 3 and 4: discovery of S/GSK364735 was a resu
Page 5 and 6: compounds was then performed target
Page 7 and 8: MEDI 13 Potent, brain-penetrant, hy
Page 9 and 10: predominately in the liver, leads t
Page 11: Candidate Optimization Department,
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
Page 61 and 62: 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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