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Frederick Cohen,
Philippe Bergeron,
Elizabeth Blackwood,
Krista K Bowman,
Huifen Chen,
Antonio G Dipasquale,
Jennifer A Epler,
Michael F T Koehler,
Kevin Lau,
Cristina Lewis, [......],
Jim Nonomiya, Daniel F Ortwine,
Zhonghua Pei,
Kirk D Robarge,
Steve Sideris,
Lan Trinh,
Tom Truong,
Jiansheng Wu,
Xianrui Zhao,
Joseph P Lyssikatos
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ABSTRACT: A series of inhibitors of mTOR kinase based on a quaternary-substituted dihydrofuropyrimidine was designed and synthesized. The most potent compounds in this series inhibited mTOR kinase with K(i) < 1.0 nM and were highly (>100×) selective for mTOR over the closely related PI3 kinases. Compounds in this series showed inhibition of the pathway and antiproliferative activity in cell-based assays. Furthermore, these compounds had excellent mouse PK, and showed a robust PK-PD relationship in a mouse model of cancer.
Journal of Medicinal Chemistry 05/2011; 54(9):3426-35. · 4.80 Impact Factor
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Anthony M Giannetti,
Harvey Wong,
Gerrit J P Dijkgraaf,
Erin C Dueber, Daniel F Ortwine,
Brandon J Bravo,
Stephen E Gould,
Emile G Plise,
Bert L Lum,
Vikram Malhi,
Richard A Graham
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ABSTRACT: Vismodegib (GDC-0449) is is an orally available selective Hedgehog pathway inhibitor in development for cancer treatment. The drug is ≥95% protein bound in plasma at clinically relevant concentrations and has an approximately 200-fold longer single dose half-life in humans than rats. We have identified a strong linear relationship between plasma drug concentrations and α-1-acid glycoprotein (AAG) in a phase I study. Biophysical and cellular techniques have been used to reveal that vismodegib strongly binds to human AAG (K(D) = 13 μM) and binds albumin with lower affinity (K(D) = 120 μM). Additionally, binding to rat AAG is reduced ∼20-fold relative to human, whereas the binding affinity to rat and human albumin was similar. Molecular docking studies reveal the reason for the signficiant species dependence on binding. These data highlight the utility of biophysical techniques in creating a comprehensive picture of protein binding across species.
Journal of Medicinal Chemistry 03/2011; 54(8):2592-601. · 4.80 Impact Factor
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Amy B Dounay,
Nancy S Barta,
Brian M Campbell,
Corey Coleman,
Elizabeth M Collantes,
Lynne Denny,
Satavisha Dutta,
David L Gray,
Dongfeng Hou,
Rathna Iyer,
Samarendra N Maiti, Daniel F Ortwine,
Al Probert,
Nancy C Stratman,
Rajendra Subedi,
Tammy Whisman,
Wenjian Xu,
Kim Zoski
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ABSTRACT: Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT(1A) partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT(1A) partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.
Bioorganic & medicinal chemistry letters 02/2010; 20(3):1114-7. · 2.65 Impact Factor
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Jeff B Smaill,
Edward N Baker,
R John Booth,
Alexander J Bridges,
James M Dickson,
Ellen M Dobrusin,
Ivan Ivanovic,
Alan J Kraker,
Ho H Lee,
Elizabeth A Lunney, Daniel F Ortwine,
Brian D Palmer,
John Quin,
Christopher J Squire,
Andrew M Thompson,
William A Denny
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ABSTRACT: A series of N-6 substituted 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds were tested for their ability to inhibit the G2/M cell cycle checkpoint kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains were potent dual inhibitors. Acidic side chains provided potent (average IC(50) 0.057 microM) and selective (average ratio 223-fold) Wee1 inhibition. Co-crystal structures of inhibitors bound to Wee1 show that the pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6 substituents involved in H-bonding to conserved water molecules. HT-29 cells treated with doxorubicin and then target compounds demonstrate an active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2 checkpoint.
European Journal of Medicinal Chemistry 07/2008; 43(6):1276-96. · 3.35 Impact Factor
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Jie Jack Li,
Joe Nahra,
Adam R Johnson,
Amy Bunker,
Patrick O'Brien,
Wen-Song Yue, Daniel F Ortwine,
Chiu-Fai Man,
Vijay Baragi,
Kenneth Kilgore,
Richard D Dyer,
Hyo-Kyung Han
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ABSTRACT: Quinazolinones 8 and pyrido[3,4-d]pyrimidin-4-ones 9 as orally active and specific matrix metalloproteinase-13 inhibitors were discovered for the treatment of osteoarthritis. Starting from a high-through-put screening (HTS) hit thizolopyrimidin-dione 7, we obtained two chemotypes, 8 and 9, using computer-aided drug design (CADD) and methodical structure-activity relationship (SAR) studies. They occupy the unique S 1'-specificity pocket and do not bind to the Zn(2+) ion. Some pyrido[3,4-d]pyrimidin-4-ones, such as 10a, possess favorable absorption, distribution, metabolism, and elimination (ADME) and safety profiles. 10a effectively prevents cartilage damage in rabbit animal models of osteoarthritis without inducing musculoskeletal side effects when given at extremely high doses to rats.
Journal of Medicinal Chemistry 03/2008; 51(4):835-41. · 5.25 Impact Factor
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Julie A Spicer,
Gordon W Rewcastle,
Michael D Kaufman,
Shannon L Black,
Mark S Plummer,
William A Denny,
John Quin,
Aurash B Shahripour,
Stephen D Barrett,
Christopher E Whitehead, [......],
Nadia Esmaeil,
Kelley Moore,
Judith S Sebolt-Leopold,
Sally Pryzbranowski,
Ronald L Merriman, Daniel F Ortwine,
Joseph S Warmus,
Cathlin M Flamme,
Alexander G Pavlovsky,
Haile Tecle
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ABSTRACT: A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate. Most notably, pyridone 27 was found to be more potent than 1 in vitro and produced a 100% response rate at a lower dose than 1, when tested for in vivo efficacy in animals bearing C26 tumors.
Journal of Medicinal Chemistry 11/2007; 50(21):5090-102. · 5.25 Impact Factor
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Adam R Johnson,
Alexander G Pavlovsky, Daniel F Ortwine,
Faith Prior,
Chiu-Fai Man,
Dirk A Bornemeier,
Craig A Banotai,
W Thomas Mueller,
Patrick McConnell,
Chunhong Yan,
Vijay Baragi,
Charles Lesch,
W Howard Roark,
Michael Wilson,
Kaushik Datta,
Roberto Guzman,
Hyo-Kyung Han,
Richard D Dyer
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ABSTRACT: Matrix metalloproteinase-13 (MMP13) is a Zn(2+)-dependent protease that catalyzes the cleavage of type II collagen, the main structural protein in articular cartilage. Excess MMP13 activity causes cartilage degradation in osteoarthritis, making this protease an attractive therapeutic target. However, clinically tested MMP inhibitors have been associated with a painful, joint-stiffening musculoskeletal side effect that may be due to their lack of selectivity. In our efforts to develop a disease-modifying osteoarthritis drug, we have discovered MMP13 inhibitors that differ greatly from previous MMP inhibitors; they do not bind to the catalytic zinc ion, they are noncompetitive with respect to substrate binding, and they show extreme selectivity for inhibiting MMP13. By structure-based drug design, we generated an orally active MMP13 inhibitor that effectively reduces cartilage damage in vivo and does not induce joint fibroplasias in a rat model of musculoskeletal syndrome side effects. Thus, highly selective inhibition of MMP13 in patients may overcome the major safety and efficacy challenges that have limited previously tested non-selective MMP inhibitors. MMP13 inhibitors such as the ones described here will help further define the role of this protease in arthritis and other diseases and may soon lead to drugs that safely halt cartilage damage in patients.
Journal of Biological Chemistry 10/2007; 282(38):27781-91. · 4.77 Impact Factor
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Brian D Palmer,
Andrew M Thompson,
R John Booth,
Ellen M Dobrusin,
Alan J Kraker,
Ho H Lee,
Elizabeth A Lunney,
Lorna H Mitchell, Daniel F Ortwine,
Jeff B Smaill,
Leesa M Swan,
William A Denny
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ABSTRACT: High-throughput screening has identified a novel class of inhibitors of the checkpoint kinase Wee1, which have potential for use in cancer chemotherapy. These inhibitors are based on a 4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione template and have been shown by X-ray crystallography to bind at the ATP site of the enzyme. An extensive study of the effects of substitution around this template has been carried out, which has identified substituents which lead to improvements in potency and selectivity for Wee1. While retention of the maleimide ring and pendant 4-phenyl group is necessary for potency, replacement of the carbazole nitrogen by oxygen is well tolerated and results in improved Wee1 selectivity against the related checkpoint kinase Chk1. Wee1 potency and selectivity are also enhanced by the incorporation of lipophilic functionality at the 2'-position of the 4-phenyl ring, and Wee1 selectivity against Chk1 is favored by C3-C5 alkyl substitution of the carbazole nitrogen. These studies provide a basis for the design of active analogues of the pyrrolocarbazole lead with improved physical properties.
Journal of Medicinal Chemistry 09/2006; 49(16):4896-911. · 5.25 Impact Factor
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[show abstract]
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ABSTRACT: For an animal model to predict a compound’s potential for treating human disease, inhibitor interactions with the cognate
enzymes of separate species must be comparable. Rabbit and human isoforms of stromelysin-1 are highly homologous, yet there
are clear and significant compound-specific differences in inhibitor potencies between these two enzymes. Using crystal structures
of discordant inhibitors complexed with the human enzyme, we generated a rabbit enzyme homology model that was used to identify
two unmatched residues near the active site that could explain the observed disparities. To test these observations, we designed
and synthesized three chimeric mutants of the human enzyme containing the single (H224N and L226F) and double (H224N/L226F)
mutations. A comparison of inhibitor potencies among the mutant and wild-type enzymes shows that the mutation of a single
amino acid in the human enzyme, histidine 224 to asparagine, is sufficient to change the selectivity profile of the mutant
to that of the rabbit isoform. These studies emphasize the importance of considering species differences, which can result
from even minor protein sequence variations, for the critical enzymes in an animal disease model. Homology modeling provides
a tool to identify key differences in isoforms that can significantly affect native enzyme activity.
Journal of Biological Chemistry 08/1999; 274(35):24881-24887. · 4.77 Impact Factor
