Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington's disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a "closed-loop" form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.

Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER + breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f ]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.

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Summary The Canary Islands and Madeira are reportedly home to seven recognised species of baetid mayflies (Ephemeroptera, Baetidae), two of which also occur on the European mainland. Their species status remains unsure, and loss of habitat suggests they are of conservation concern. We applied morphological characters and a general mixed Yule‐coalescent (gmyc) model analysis of the cytochrome c oxidase subunit 1 (cox1) gene to delineate putative species within morphologically cryptic species groups Baetis (Rhodobaetis) and Cloeon dipterum s.l. We used a three‐gene mitochondrial data set (1450 base pairs) to infer phylogenetic relationships and a molecular clock calibrated using island geological ages to infer colonisation history. Genetic and morphological evidence indicated the presence of 12 putative species, 11 of which were endemic to the islands. Only Baetis atlanticus, on Madeira, also occurs on the European mainland. Two lineages (B. pseudorhodani s.l. and B. canariensis s.l.) appear to have arisen in the past 15 million years (mya) and diversified in parallel throughout the Canary Islands. Within the canariensis lineage, sister species occur on the island of Gran Canaria and in North Africa. Pronounced island endemism contradicts previous taxonomic work, which reported a depauperate fauna that included several mainland species. Recent diversification among islands and a close link to North Africa suggest a complex evolutionary history. Owing to their small population size and ongoing habitat alteration, several of these island endemics are among the most endangered aquatic insects in Europe.

This paper describes the identification and optimization of a novel series of DFG-out binding p38 inhibitors as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure based drug design and "inhalation by design" principles have been applied to the optimization of the lead series exemplied by compound 1a. Analogues have been designed to be potent and selective for p38, with an emphasis on slow enzyme dissociation kinetics to deliver prolonged lung p38 inhibition. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimize systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance and glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimize drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity, and solubility were considered to ensure compatibility with a dry powder inhaler. 1ab (PF-03715455) was subsequently identified as a clinical candidate from this series with efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of COPD.