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Phenolic groups are responsible for the high clearance and low oral bioavailability of the estrogen receptor alpha (ERα) clinical candidate GDC-0927. An exhaustive search for a backup molecule with improved pharmacokinetic (PK) properties identified several metabolically stable analogs, although in general at the expense of the desired potency and degradation efficiency. C-8 hydroxychromene 30 is the first example of a phenol-containing chromene that not only maintained excellent potency but also exhibited 10-fold higher oral exposure in rats. The improved in vivo clearance in rat was hypothesized to be the result of C-8 hydroxy group being sterically protected from glucuronide conjugation. The excellent potency underscores the possibility of replacing the presumed indispensable phenolic group at C-6 or C-7 of the chromene core. Co-crystal structures were obtained to highlight the change in key interactions and rationalize the retained potency.

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.

We report the optimization of a series of non-steroidal GR antagonists that led to the identification of compound 7. This compound is efficacious when dosed orally in an olanzapine-induced weight gain model in rats.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that is a leading cause of morbidity and mortality worldwide with an overall prevalence in adults >40 years estimated at 9–10%. The World Health Organization (WHO) estimates that, by 2020, COPD will be the third leading cause of mortality and the fifth leading cause of morbidity in the world. This smoking-related disease is characterized by progressive airway obstruction that, unlike asthma, is relatively insensitive to bronchodilators and to the classic anti-inflammatory therapy, corticosteroids. Current therapy focuses mainly on reducing symptoms using inhaled short-acting and long-acting bronchodilators either as monotherapies or in combination with inhaled corticosteroids. During the last decade, the pharmaceutical industry has focused on treating COPD distinctly from asthma but no novel agents that target the disease itself have been launched as therapies for this disease. As our understanding of the pathology of COPD has increased it has been established that the progressive pulmonary inflammation that is associated with COPD relates to disease severity. Thus, it is anticipated that drugs that reduce pulmonary inflammation will provide effective, disease-modifying therapies. Here, we consider the potential of anti-inflammatory drugs that are currently in clinical development for COPD and discuss how these might reduce pulmonary inflammation in this disease. Keywords: anti-inflammatory; bronchodilator; COPD; inhaled corticosteroid; muscarinic

Since the discovery and characterisation of melanin-concentrating hormone (MCH) and its role in the regulation of food intake and energy expenditure, there has been increasing interest in this cyclic peptide. The identification of the MCH-1 receptor (MCH-1R) in 1999 initiated the search for small molecules that could block the effects of MCH and provide novel agents for the treatment of obesity. A large number of companies is now actively pursuing MCH-1R antagonists and a wide range of structural types have been reported. Several compounds have been reported to be efficacious in rodent models of obesity and two compounds have recently entered into human clinical trials.

The development of a series of novel quinazolinethiones and quinazolinediones as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II and in vitro inhibitory value for PBMC proliferation are discussed.

Perfluoro-3-methylpent-2-ene (tetrafluoroethylene (TFE) trimer) (1) , produced by the flash vacuum thermolysis (FVT) of perfluoro-2,3-epoxy-4-ethyl-2, 3,4,5-tetramethyl-4,5-dihydrofuran was reacted with a range of monoand bidentate nucleophiles to give partially fluorinated products. The position of attack was found to be nucleophile dependent.

An enantioselective synthesis of (R)-mevalonolactone (1) has been accomplished starting from known epoxide 2, prepared with ⪢95% ee by asymmetric epoxidation of nerol. Functional group manipulation of 2 and ozonolysis afforded intermediate 8, which was converted to 11 via phenylselenoxide formation, followed by appropriate oxidations and deprotection, to afford 1.

An enantioselective synthesis of (R)-mevalonolactone (1) has been accomplished starting from known epoxide 2, prepared with ⪢95% ee by asymmetric epoxidation of nerol. Functional group manipulation of 2 and ozonolysis afforded intermediate 8, which was converted to 11 via phenylselenoxide formation, followed by appropriate oxidations and deprotection, to afford 1.

The proven efficacy of several anti-cholinergics and beta(2)-agonists and their combinations in both chronic obstructive pulmonary disease (COPD) and asthma strongly validates this therapeutic approach. As a consequence and although technically challenging, over the past 4 years there has been a growing interest in the generation of dual pharmacology Muscarinic-receptor antagonists-beta(2)-adrenergic receptor agonists (MABAs) for the treatment of COPD.This article surveys and reviews the research activity in the MABA area to the end of August 2008.Although the activity in this field seems to still be limited to a few companies, significant progress in the discovery of a MABA has been achieved with the progression of at least one candidate (GSK-961081) to the clinic.

The perfluorinated dihydrofuran, perfluoro-4-ethyl-2,3,4,5-tetramethyl-4,5- dihydrofuran PFDHF (1), prepared from tetratluoroethene pentamer, was reacted with a range of nucleophiles. The type of product formed was found to be dependant upon the nucleophile used. Attack with oxygen, sulphur and carbon nucleophiles was found to occur at the 2-position, whereas nitrogen nucleophiles were found to attack at either the 2- position or the exocyclic 3-position.

Three 7,7-disubstituted derivatives (2,3, and 4) of the oxido-squalene cyclase inhibitor TMD (1) have been synthesized.

Addition of the 4-fluorophenylpyrazole group to the previously described 2-azadecalin glucocorticoid receptor (GR) antagonist 1 resulted in significantly enhanced functional activity. SAR of the bridgehead substituent indicated that whereas groups as small as methyl afforded high GR binding, GR functional activity was enhanced by larger groups such as benzyl, substituted ethers, and aminoalkyl derivatives. GR antagonists with binding and functional activity comparable to mifepristone were discovered (e.g., 52: GR binding Ki 0.7 nM; GR reporter gene functional Ki 0.6 nM) and found to be highly selective over other steroid receptors. Analogues 43 and 45 had >50% oral bioavailability in the dog.

A virtual screening approach comprising a 3-D similarity search based on known GR modulators was used to identify a novel series of non-steroidal glucocorticoid receptor (GR) antagonists. Optimization of the initial hit to provide potent compounds which exhibit good selectivity against other steroidal nuclear hormone receptors is described.

The 2-azadecalin ring system was evaluated as a scaffold for the preparation of glucocorticoid receptor (GR) antagonists. High affinity, selective GR antagonists were discovered based on a hypothetical binding mode related to the steroidal GR antagonist RU-43044. 2-Benzenesulfonyl substituted 8a-benzyl-hexahydro-2H-isoquinolin-6-ones exemplified by (R)-37 had low nanomolar affinity for GR with moderate functional activity (200 nM) in a reporter gene assay. These compounds were devoid of affinity for other steroidal receptors (ER, AR, MR, and PR). Analogues based on an alternative putative binding mode (CP-like) were found to be inactive.

The synthesis and biological activity of a novel series of 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones are described. Some of these compounds were found to be potent inhibitors of inosine 5'-monophosphate dehydrogenase type II (IMPDH II).

[reaction: see text] A new method for the solid-phase synthesis of cyanamides is described. The attachment of a secondary amine to solid support is accomplished using Merrifield resin. After functionalization, cleavage is readily achieved with cyanogen bromide to afford the desired cyanamide.

The ketene (1) is a remarkably stable aldoketene derived from T.F.E. pentamer by the reaction with strong base and then by dehydration of the resulting acid-- The ketene is readily isolable and does not dimerise, although it reacts rapidly with a wide range of nucleophiles. The paper will describe a range of cycloaddition reactions with CC, CO and CN systems. The type of product obtained depends on the structure of the addend and reasons for this and a comparison with hydrocarbon analogues will be discussed.