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861.
David M. Wilson James Apps Nicholas Bailey Mark J. Bamford Isabel J. Beresford Michael A. Briggs Andrew R. Calver Barry Crook Robert P. Davis Susannah Davis David K. Dean Leanne Harris Tom D. Heightman Terry Panchal Christopher A. Parr Nigel Quashie Jon G.A. Steadman Joanne Schogger Andrew D. Medhurst 《Bioorganic & medicinal chemistry letters》2013,23(24):6897-6901
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties. 相似文献
862.
Antonio Mete Keith Bowers Richard J. Bull Helen Coope David K. Donald Katherine J. Escott Rhonan Ford Ken Grime Andrew Mather Nicholas C. Ray Vince Russell 《Bioorganic & medicinal chemistry letters》2013,23(23):6248-6253
A novel series of muscarinic receptor antagonists was developed, with the aim of identifying a compound with high M3 receptor potency and a reduced risk of dose-limiting side effects with potential for the treatment of COPD.Initial compound modifications led to a novel cycloheptyl series, which was improved by focusing on a quinuclidine sub-series. A wide range of N-substituents was evaluated to determine the optimal substituent providing a high M3 receptor potency, high intrinsic clearance and high human plasma protein binding. Compounds achieving in vitro study criteria were selected for in vivo evaluation. Pharmacokinetic half-lives, inhibition of bronchoconstriction and duration of action, as well as systemic side effects, induced by the compounds were assessed in guinea-pig models.Compounds with a long duration of action and good therapeutic index were identified and AZD8683 was selected for progression to the clinic. 相似文献
863.
Andrew S. Rosenthal Thomas S. Dexheimer Opher Gileadi Giang H. Nguyen Wai Kit Chu Ian D. Hickson Ajit Jadhav Anton Simeonov David J. Maloney 《Bioorganic & medicinal chemistry letters》2013,23(20):5660-5666
Human cells utilize a variety of complex DNA repair mechanisms in order to combat constant mutagenic and cytotoxic threats from both exogenous and endogenous sources. The RecQ family of DNA helicases, which includes Bloom helicase (BLM), plays an important function in DNA repair by unwinding complementary strands of duplex DNA as well as atypical DNA structures such as Holliday junctions. Mutations of the BLM gene can result in Bloom syndrome, an autosomal recessive disorder associated with cancer predisposition. BLM-deficient cells exhibit increased sensitivity to DNA damaging agents indicating that a selective BLM inhibitor could be useful in potentiating the anticancer activity of these agents. In this work, we describe the medicinal chemistry optimization of the hit molecule following a quantitative high-throughput screen of >355,000 compounds. These efforts lead to the identification of ML216 and related analogs, which possess potent BLM inhibition and exhibit selectivity over related helicases. Moreover, these compounds demonstrated cellular activity by inducing sister chromatid exchanges, a hallmark of Bloom syndrome. 相似文献
864.
Mathivanan Packiarajan Michel Grenon Samuel Zorn Allen T. Hopper Andrew D. White Gamini Chandrasena Xiaosui Pu Robbin M. Brodbeck Albert J. Robichaud 《Bioorganic & medicinal chemistry letters》2013,23(14):4037-4043
A new series of potent fused thiazole mGlu5 receptor positive allosteric modulators (PAMs) (10, 11 and 27–31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification of potent fused thiazole analogs 10b, 27a, 28j and 31d. In general, substituted cycloalkyl, aryl and heteroaryl carboxamides, and carbamate analogs are mGlu5 PAMs, whereas smaller alkyl carboxamide, sulfonamide and sulfamide analogs tend to be mGlu5 negative allosteric modulators (NAMs). 相似文献
865.
Andrew M.K. Pennell James B. Aggen Subhabrata Sen Wei Chen Yuan Xu Edward Sullivan Lianfa Li Kevin Greenman Trevor Charvat Derek Hansen Daniel J. Dairaghi J.J. Kim Wright Penglie Zhang 《Bioorganic & medicinal chemistry letters》2013,23(5):1228-1231
A novel series of CCR1 antagonists based on the 1-(4-phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanone scaffold was identified by screening a compound library utilizing CCR1-expressing human THP-1 cells. SAR studies led to the discovery of the highly potent and selective CCR1 antagonist 14 (CCR1 binding IC50 = 4 nM using [125I]-CCL3 as the chemokine ligand). Compound 14 displayed promising pharmacokinetic and toxicological profiles in preclinical species. 相似文献
866.
Shoujun Chen Lijun Sun Keizo Koya Noriaki Tatsuta Zhiqiang Xia Timothy Korbut Zhenjian Du Jim Wu Guiqing Liang Jun Jiang Mitsunori Ono Dan Zhou Andrew Sonderfan 《Bioorganic & medicinal chemistry letters》2013,23(18):5070-5076
A series of N′1,N′3-dialkyl-N′1,N′3-di(alkylcarbonothioyl) malonohydrazides have been designed and synthesized as anticancer agents by targeting oxidative stress and Hsp70 induction. Structure–activity relationship (SAR) studies lead to the discovery of STA-4783 (elesclomol), a novel small molecule that has been evaluated in a number of clinical trials as an anticancer agent in combination with Taxol. 相似文献
867.
Colin A. Lowery Michael Adler Andrew Borrell Kim D. Janda 《Bioorganic & medicinal chemistry letters》2013,23(24):6743-6746
The botulinum neurotoxins, characterized by their neuromuscular paralytic effects, are the most toxic proteins known to man. Due to their extreme potency, ease of production, and duration of activity, the BoNT proteins have been classified by the Centers for Disease Control as high threat agents for bioterrorism. In an attempt to discover effective BoNT therapeutics, we have pursued a strategy in which we leverage the blockade of K+ channels that ultimately results in the reversal of neuromuscular paralysis. Towards this end, we utilized peptides derived from scorpion venom that are highly potent K+ channel blockers. Herein, we report the synthesis of charybdotoxin, a 37 amino acid peptide, and detail its activity, along with iberiotoxin and margatoxin, in a mouse phrenic nerve hemidiaphragm assay in the absence and the presence of BoNT/A. 相似文献
868.
Xiaojun Han Rita L. Civiello Charles M. Conway Deborah A. Cook Carl D. Davis Andrew P. Degnan Xiang-Jun Jiang Robert Macci Neil R. Mathias Paul Moench Sokhom S. Pin Richard Schartman Laura J. Signor George Thalody George Tora Valerie Whiterock Cen Xu John E. Macor Gene M. Dubowchik 《Bioorganic & medicinal chemistry letters》2013,23(12):3674
869.
Compelling data supports the hypothesis that Pin1 inhibitors will be useful for the therapy of cancer: Pin1 deficient mice resist the induction of breast cancers normally evoked by expression of MMTV-driven Ras or Erb2 alleles. While Pin1 poses challenges for drug discovery, several groups have identified potent antagonists by structure based drug design, significant progress has been made designing peptidic inhibitors and a number of natural products have been found that blockade Pin1, notably epigallocatchechin gallate (EGCG), a major flavonoid in green tea. Here we critically discuss the modes of action and likely specificity of these compounds, concluding that a suitable chemical biology tool for probing the function of Pin1 has yet to be found. We conclude by outlining some open questions regarding the target validation of Pin1 and the prospects for identification of improved inhibitors in the future. 相似文献
870.
Daryl R. Trumbo Stephen F. Spear Jason Baumsteiger Andrew Storfer 《Molecular ecology》2013,22(5):1250-1266
A species' genetic structure often varies in response to ecological and landscape processes that differ throughout the species' geographic range, yet landscape genetics studies are rarely spatially replicated. The Cope's giant salamander (Dicamptodon copei) is a neotenic, dispersal‐limited amphibian with a restricted geographic range in the Pacific northwestern USA. We investigated which landscape factors affect D. copei gene flow in three regions spanning the species' range, which vary in climate, landcover and degree of anthropogenic disturbance. Least cost paths and Circuitscape resistance analyses revealed that gene flow patterns vary across the species' range, with unique combinations of landscape variables affecting gene flow in different regions. Populations in the northern coastal portions of the range had relatively high gene flow, largely facilitated by stream and river networks. Near the southeastern edge of the species' range, gene flow was more restricted overall, with relatively less facilitation by streams and more limitation by heat load index and fragmented forest cover. These results suggested that the landscape is more difficult for individuals to disperse through at the southeastern edge of the species' range, with terrestrial habitat desiccation factors becoming more limiting to gene flow. We suggest that caution be used when attempting to extrapolate landscape genetic models and conservation measures from one portion of a species' range to another. 相似文献