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961.
Kirk D. Robarge Shirley A. Brunton Georgette M. Castanedo Yong Cui Michael S. Dina Richard Goldsmith Stephen E. Gould Oivin Guichert Janet L. Gunzner Jason Halladay Wei Jia Cyrus Khojasteh Michael F.T. Koehler Karen Kotkow Hank La Rebecca L. LaLonde Kevin Lau Leslie Lee Derek Marshall James C. Marsters Minli Xie 《Bioorganic & medicinal chemistry letters》2009,19(19):5576-5581
SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5 mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC. 相似文献
962.
Mark J. Ammirati Kim M. Andrews David D. Boyer Anne M. Brodeur Dennis E. Danley Shawn D. Doran Bernard Hulin Shenping Liu R. Kirk McPherson Stephen J. Orena Janice C. Parker Jana Polivkova Xiayang Qiu Carolyn B. Soglia Judith L. Treadway Maria A. VanVolkenburg Donald C. Wilder David W. Piotrowski 《Bioorganic & medicinal chemistry letters》2009,19(7):1991-1995
A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC50 = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes. 相似文献
963.
Sabbir Ahmed Imran Shahid Sachin Dhanani Caroline P. Owen 《Bioorganic & medicinal chemistry letters》2009,19(16):4698-4701
We report the synthesis and biochemical evaluation of a range of 4-sulfonated derivatives of 4-hydroxybenzyl imidazole which has been targetted against the two components of 17α-hydroxylase/17,20-lyase (P-45017α), namely, 17α-hydroxylase (17α-OHase) and 17,20-lyase (lyase). The results from the biochemical testing suggest that the compounds synthesised are highly potent inhibitors possessing excellent selectivity towards the lyase component. 相似文献
964.
Robert O. Hughes John K. Walker D. Joseph Rogier Steve E. Heasley Rhadika M. Blevis-Bal Alan G. Benson E. Jon Jacobsen Jerry W. Cubbage Yvette M. Fobian Dafydd R. Owen John N. Freskos John M. Molyneaux David L. Brown Brad A. Acker Todd M. Maddux Mike B. Tollefson Joseph B. Moon Brent V. Mischke Jeanne M. Rumsey Yi Zheng Ying Yu 《Bioorganic & medicinal chemistry letters》2009,19(17):5209-5213
We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile. 相似文献
965.
Maheshinie Rajapaksha Jack F. Eichler Jan Hajduch David E. Anderson Kenneth L. Kirk James G. Bann 《Protein science : a publication of the Protein Society》2009,18(1):17-23
The binding of the Bacillus anthracis protective antigen (PA) to the host cell receptor is the first step toward the formation of the anthrax toxin, a tripartite set of proteins that include the enzymatic moieties edema factor (EF), and lethal factor (LF). PA is cleaved by a furin‐like protease on the cell surface followed by the formation of a donut‐shaped heptameric prepore. The prepore undergoes a major structural transition at acidic pH that results in the formation of a membrane spanning pore, an event which is dictated by interactions with the receptor and necessary for entry of EF and LF into the cell. We provide direct evidence using 1‐dimensional 13C‐edited 1H NMR that low pH induces dissociation of the Von‐Willebrand factor A domain of the receptor capillary morphogenesis protein 2 (CMG2) from the prepore, but not the monomeric full length PA. Receptor dissociation is also observed using a carbon‐13 labeled, 2‐fluorohistidine labeled CMG2, consistent with studies showing that protonation of His‐121 in CMG2 is not a mechanism for receptor release. Dissociation is likely caused by the structural transition upon formation of a pore from the prepore state rather than protonation of residues at the receptor PA or prepore interface. 相似文献
966.
Linda J.S. Allen Curtis L. Wesley Robert D. Owen Douglas G. Goodin David Koch Colleen B. Jonsson Yong-Kyu Chu J.M. Shawn Hutchinson Robert L. Paige 《Journal of theoretical biology》2009,260(4):510-522
New habitat-based models for spread of hantavirus are developed which account for interspecies interaction. Existing habitat-based models do not consider interspecies pathogen transmission, a primary route for emergence of new infectious diseases and reservoirs in wildlife and man. The modeling of interspecies transmission has the potential to provide more accurate predictions of disease persistence and emergence dynamics. The new models are motivated by our recent work on hantavirus in rodent communities in Paraguay. Our Paraguayan data illustrate the spatial and temporal overlaps among rodent species, one of which is the reservoir species for Jabora virus and others which are spillover species. Disease transmission occurs when their habitats overlap. Two mathematical models, a system of ordinary differential equations (ODE) and a continuous-time Markov chain (CTMC) model, are developed for spread of hantavirus between a reservoir and a spillover species. Analysis of a special case of the ODE model provides an explicit expression for the basic reproduction number, , such that if , then the pathogen does not persist in either population but if , pathogen outbreaks or persistence may occur. Numerical simulations of the CTMC model display sporadic disease incidence, a new behavior of our habitat-based model, not present in other models, but which is a prominent feature of the seroprevalence data from Paraguay. Environmental changes that result in greater habitat overlap result in more encounters among various species that may lead to pathogen outbreaks and pathogen establishment in a new host. 相似文献
967.
Stevens C Lin Y Harrison B Burch L Ridgway RA Sansom O Hupp T 《The Journal of biological chemistry》2009,284(1):334-344
Death-associated protein kinase (DAPK) is a multidomain enzyme that plays a central role in autophagic and apoptotic signaling, although the protein-protein interactions regulating DAPK functions are not well defined. Peptide aptamer libraries were used to identify the tumor suppressor protein tuberin (TSC2) as a novel DAPK death domain-binding protein, and we evaluated whether DAPK is a positive or negative effector of the TSC2-regulated mammalian target of rapamycin (mTORC1) signaling pathway. Binding studies using death domain miniproteins in vitro and deletion analysis in vivo determined that the death domain of DAPK is the major site for the interaction with TSC2. Recombinant DAPK phosphorylates TSC2 in vitro, and DAPK kinase activity is stimulated by growth factor signaling. Transfection of DAPK promotes phosphorylation of TSC2 in vivo, whereas short interfering RNA-mediated attenuation of DAPK reduces growth factor-stimulated phosphorylation of TSC2. DAPK-dependent phosphorylation leads to TSC1-TSC2 complex dissociation, and consequently manipulation of DAPK by transfection or short interfering RNA demonstrated that DAPK is a positive regulator of mTORC1 in response to growth factor activation. Epistatic studies suggest that DAPK functions downstream from the RAS-MEK-ERK and phosphatidylinositol 3-kinase-AKT growth factor signaling pathways. DAPK(+/-) mouse embryo fibroblasts have attenuated mTORC1 signaling compared with DAPK+/+ counterparts, and overexpression of DAPK in DAPK(+/-) MEFs stimulates mTORC1 activity. These data uncover a novel interaction between DAPK and TSC2 proteins that has revealed a positive link between growth factor stimulation of DAPK and mTORC1 signaling that may ultimately affect autophagy, cell survival, or apoptosis. 相似文献
968.
969.
Matt Turner Seth Eidemiller Bryan Martin Andrew Narver Joshua Marshall Logan Zemp Kenneth A. Cornell J.M. McIntosh Owen M. McDougal 《Bioorganic & medicinal chemistry》2009,17(16):5894-5899
Parkinson’s disease is a debilitating movement disorder characterized by altered levels of α6β21 (1 indicates the possible presence of additional subunits) nicotinic acetylcholine receptors (nAChRs) localized on presynaptic striatal catecholaminergic neurons. α-Conotoxin MII (α-CTx MII) is a highly useful ligand to probe α6β2 nAChRs structure and function, but it does not discriminate among closely related α61 nAChR subtypes. Modification of the α-CTx MII primary sequence led to the identification of α-CTx MII[E11A], an analog with 500–5300-fold discrimination between α61 subtypes found in both human and non-human primates. α-CTx MII[E11A] binds most strongly (femtomolar dissociation constant) to the high affinity α6 nAChR, a subtype that is selectively lost in Parkinson’s disease. Here, we present the three-dimensional solution structure for α-CTx MII[E11A] as determined by two-dimensional 1H NMR spectroscopy to 0.13 ± 0.09 ? backbone and 0.45 ± 0.08 ? heavy atom root-mean-square deviation from mean structure. Structural comparisons suggest that the increased hydrophobic area of α-CTx MII[E11A] relative to other members of the α-CTx family may be responsible for its exceptionally high affinity for α6α4β21 nAChR as well as discrimination between α6β2 and α3β2 containing nAChRs. This finding may enable the rational design of novel peptide analogs that demonstrate enhanced specificity for α61 nAChR subunit interfaces and provide a means to better understand nAChR structural determinants that modulate brain dopamine levels and the pathophysiology of Parkinson’s disease. 相似文献
970.
Helen C. Rees Ben C. Maddison Jonathan P. Owen Garry C. Whitelam Kevin C. Gough 《Molecular biotechnology》2009,41(3):254-262
Reagents that can precipitate the disease-associated prion protein (PrPSc) are vital for the development of high sensitivity tests to detect low levels of this disease marker in biological material.
Here, a range of minerals are shown to precipitate both ovine cellular prion protein (PrPC) and ovine scrapie PrPSc. The precipitation of prion protein with silicon dioxide is unaffected by PrPSc strain or host species and the method can be used to precipitate bovine BSE. This method can reliably concentrate protease-resistant
ovine PrPSc (PrPres) derived from 1.69 μg of brain protein from a clinically infected animal diluted into either 50 ml of buffer or 15 ml of
plasma. The introduction of a SiO2 precipitation step into the immunological detection of PrPres increased detection sensitivity by over 1,500-fold. Minerals such as SiO2 are readily available, low cost reagents with generic application to the concentration of diseases-associated prion proteins. 相似文献