Synthesis and evaluation of 4-cycloheptylphenols as selective Estrogen receptor-ß agonists (SERBAs).

A short and efficient route to 4-(4-hydroxyphenyl)cycloheptanemethanol was developed, which resulted in the preparation of a mixture of 4 stereoisomers. The stereoisomers were separated by preparative HPLC, and two of the stereoisomers identified by X-ray crystallography. The stereoisomers, as well as a small family of 4-cycloheptylphenol derivatives, were evaluated as estrogen receptor-beta agonists. The lead compound, 4-(4-hydroxyphenyl)cycloheptanemethanol was selective for activating ER relative to seven other nuclear hormone receptors, with 300-fold selectivity for the ß over α isoform and with EC50 of 30-50 nM in cell-based and direct binding assays.

The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD.

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.

Fragrance material review on 1-(2,5,5-trimethylcycloheptyl)ethan-1-one.

A toxicologic and dermatologic review of 1-(2,5,5-trimethylcycloheptyl)ethan-1-one when used as a fragrance ingredient is presented. 1-(2,5,5-Trimethylcycloheptyl)ethan-1-one is a member of the fragrance structural group Alkyl Cyclic Ketones. These fragrances can be described as being composed of an alkyl, R1, and various substituted and bicyclic saturated or unsaturated cyclic hydrocarbons, R2, in which one of the rings may include up to 12 carbons. Alternatively, R2 may be a carbon bridge of C2-C4 carbon chain length between the ketone and cyclic hydrocarbon. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 1-(2,5,5-trimethylcycloheptyl)ethan-1-one were evaluated then summarized and includes physical properties, skin irritation, mucous membrane (eye) irritation, and skin sensitization data. A safety assessment of the entire Alkyl Cyclic Ketones will be published simultaneously with this document; please refer to Belsito et al. (Belsito, D., Bickers, D., Bruze, M., Calow, P., Dagli, M., Fryer, A.D., Greim, H., Miyachi, Y., Saurat, J.H., Sipes, I.G., 2013. A toxicologic and dermatologic assessment of alkyl cyclic ketones when used as fragrance ingredients. (submitted for publication)) for an overall assessment of the safe use of this material and all Alkyl Cyclic Ketones in fragrances.

Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase.

Anaplastic lymphoma kinase (ALK) is a promising therapeutic target for the treatment of cancer, supported by considerable favorable preclinical and clinical activities over the past several years and culminating in the recent FDA approval of the ALK inhibitor crizotinib. Through a series of targeted modifications on an ALK inhibitor diaminopyrimidine scaffold, our research group has driven improvements in ALK potency, kinase selectivity, and overall pharmaceutical properties. Optimization of this scaffold has led to the identification of a potent and efficacious inhibitor of ALK, 25b. A striking feature of 25b over previously described ALK inhibitors is its >600-fold selectivity over insulin receptor (IR), a closely related kinase family member. Most importantly, 25b exhibited dose proportional escalation in rat compared to compound 3 which suffered dose limiting absorption preventing further advancement. Compound 25b exhibited significant in vivo antitumor efficacy when dosed orally in an ALK-positive ALCL tumor xenograft model in SCID mice, warranting further assessment in advanced preclinical models.

[Research progress of selective mGluR1 antagonists].

As an important member of metabotropic glutamate receptors (mGluR), metabotropic glutamate receptor 1 (mGluR1) plays an important role in the signal transduction of central nervous system. Selective mGluR1 antagonists can block the signaling pathway activated by mGluR1 and exert a series of physiological actions including analgesia, antianxiety, antidepression, etc. Currently, the discovery and modification of selective mGluR1 antagonists have become a hot research focus. This paper reviews the structural catalogs of selective mGluR1 antagonists and their structure-activity relationships in the last decade.

Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor.

A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.

Antinociceptive profile of a selective metabotropic glutamate receptor 1 antagonist YM-230888 in chronic pain rodent models.

Metabotropic glutamate receptor 1 (mGlu(1) receptor) has been suggested to play an important role in pain transmission. In this study, the effects of a newly-synthesized mGlu(1) receptor antagonist, (R)-N-cycloheptyl-6-({[(tetrahydro-2-furyl)methyl]amino}methyl)thieno[2,3-d]pyrimidin-4-ylamine (YM-230888), were examined in a variety of rodent chronic pain models in order to characterize the potential analgesic profile of mGlu(1) receptor blockade. YM-230888 bound an allosteric site of mGlu(1) receptor with a K(i) value of 13+/-2.5 nM and inhibited mGlu(1)-mediated inositol phosphate production in rat cerebellar granule cells with an IC(50) value of 13+/-2.4 nM. It showed selectivity for mGlu(1) versus mGlu(2)-mGlu(7) subtypes and ionotropic glutamate receptors. YM-230888 recovered mechanical allodynia with an ED(50) value of 8.4 mg/kg p.o. in L5/L6 spinal nerve ligation models. It also showed antinociceptive response at doses of 10 and 30 mg/kg p.o. in streptozotocin-induced hyperalgesia models. In addition, it significantly reduced pain parameters at a dose of 30 mg/kg p.o. in complete Freund's adjuvant-induced arthritic pain models. Although YM-230888 showed no significant effect on rotarod performance time at doses of 10 or 30 mg/kg p.o., it significantly decreased it at a dose of 100 mg/kg p.o. On the other hand, YM-230888 showed no significant sedative effect in locomotor activity measurement up to 100 mg/kg p.o. These results suggest that the blockade of mGlu(1) receptors is an attractive target for analgesics. YM-230888 has potential as a new analgesic agent for the treatment of various chronic pain conditions. In addition, YM-230888 may be a useful tool for the investigation of mGlu(1) receptors.

SAR study of bicyclo[4.1.0]heptanes as melanin-concentrating hormone receptor R1 antagonists: taming hERG.

To improve the ex vivo potency of MCH inhibitor 1a and to address its hERG liability, a structure-activity study was carried out, focusing on three regions of the lead structure. Introduction of new side chains with basic nitrogen improved in vitro and ex vivo bindings. Many potent compounds with K(i)<10nM were discovered (compounds 6a-j) and several compounds (14-17) had excellent ex vivo binding at 6h and 24h. Attenuating the basicity of nitrogen on the side chain, and in particular, introduction of a polar group such as aminomethyl on the distal phenyl ring significantly lowered the hERG activity. Further replacement of the distal phenyl group with heteroaryl groups in the cyclohexene series provided compounds such as 28l with excellent ex vivo activity with much reduced hERG liability.

Eberconazole cream: topical and general tolerability, sensitisation potential, and systemic availability.

Eberconazole is a topical imidazole derivative, which has shown high potency against dermatophytes and yeasts (several species of Candida, Malassezia) in vitro and in experimental models. Clinical trials have found that the compound has a high degree of efficacy against dermatophytes and good tolerability. Evaluation of its a) topical and general tolerability, b) eventual development of sensitisation, c) local availability, and d) degree of systemic absorption. Two clinical trials with 28 healthy young volunteers of both sexes were performed. In Study I, placebo or eberconazole cream (2%) were applied at increasing doses: day 1 (0.5 g), days 2-3 (1 g), days 4-5 (2 g), days 6-7 (4 g), days 8-9 (8 g), and days 10-11 (12 g). On day 1, each application area was washed with ethanol-soaked gauzes at different times to assess availability of the active compound. In Study II, eberconazole cream (1%) was applied on day 1 and again at least one week later. After the first application, blood and urine samples were obtained at different times to assess systemic absorption. The only change observed was slight redness in a few volunteers after both active and placebo applications. This remitted spontaneously without intervention and we were able to continue with the administration of repeated increasing-doses. A few participants described side effects; these were all of mild intensity, and occurred in areas where placebo or eberconazole were applied, mainly within the first hour postapplication. The most frequent effect after the first application was coldness, and after repeated increasing-doses there was itching. No signs or symptoms of skin reactivity were observed following reexposure to the product. No clinically relevant changes were observed in vital signs (systolic and diastolic blood pressure, heart rate, body temperature), ECG, or analytical parameters (clinical haematology and biochemistry). The quantity of compound collected through washing gauzes decreased progressively over time. Plasma and urine concentrations of eberconazole were below the quantification limit of the analytical method (5 ng/ml) at all times. Eberconazole cream is a topical antimycotic drug that has good local and general tolerability. It has acceptable topical availability, no detectable systemic drug levels, and does not appear to cause skin sensitivity.

Discovery and SAR of potent, orally available and brain-penetrable 5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen- and 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen derivatives as neuropeptide Y Y5 receptor antagonists.

Combination of structural elements from a potent Y5 antagonist (2) with thiazole fragments that exhibit weak Y5 affinities followed by lead optimisation led to the discovery of (5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino and (4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino derivatives. Both classes of compounds are capable of delivering potent and selective orally and centrally bioavailable NPY Y5 receptor antagonists.

Azulene incorporation and release by hydrogel containing methacrylamide propyltrimenthylammonium chloride, and its application to soft contact lens.

We have developed the epoch-making contact lens that is equipped with drug delivery system. The hydrogels contain cationic functional group in its side chain were prepared with 2-hydroxyethyl methacylate (HEMA) and methacrylamide propyltrimethylammonium chloride (MAPTAC). The obtained hydrogel is capable to store the anionic drug such as azulene based on ion-exchange reaction. The incorporated anionic drug would be released in physiological condition. The size change of the hydrogel may occur before and after drug release, but we have discovered that the addition of anionic monomer such as methacrylic acid (MAA) and 2-methacryloxyethyl acid phosphate (MOEP) to the above-mentioned composition is effective to prevent the size change, indicating that this hydrogel has the possibility to be applied as a significant drug delivery system device.

4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivatives as anti-tumor agents.

A series of naturally occurring and synthetic novel oxapenam (4-oxa-1-azabicyclo[3.2.0] heptan-7-one) derivatives with their antitumor activity and the structure-activity relationship among this class of compounds is reported. Among the synthetic 4-oxa-1-azabicyclo[3.2.0]heptan-7-one having an ester, amide, ether derivatives of hydroxy group at C-3 position exhibited either no activity or reduced the antitumor activity in vitro. The 3-amino acid 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivatives showed better antitumor activity than naturally occurring 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivative G0069A. The trans isomers exhibited superior stability and activity over the cis isomers at the 3- and 5-position. Some of these compounds showed strong cytotoxicity against P388 and KB cells with IC(50) value ranging from 0.004 to 0.6 micro g/ml and they did not show any cross resistance against ADR, 5-FU and VCR resistant cell lines in vitro. Of these, 3-hydroxy methyl, 3-(2-amino-2-carboxy-1-benzyloxy ethyl) and 3-(2-amino-2-carboxy ethyl) 4-oxa-1-azabicyclo[3.2.0] heptan-7-one inhibited 71-84% in vivo tumor growth of colon 26 and S-180 cells subcutaneously implanted into mice at a varying dose between 0.625-15 mg/kg/day depending upon the compounds and the tumor cell lines.

In vitro anti-multidrug resistance activities of acyclic and cyclic disulfonamides in murine leukemia cells.

We synthesized seven acyclic ethylenedisulfonamides and twelve cyclic disulfonamides, 1, 5-bis(arenesulfonyl)-1, 3, 5-triazacycloheptanes, and compared their in vitro anti-multidrug resistance effects in P388/ADR multidrug-resistant cells which overexpress the multidrug transporter P-glycoprotein (P-gp). Acyclic disulfonamides with 4-methoxyphenyl, pyridyl, quinolyl, or isoquinolyl groups hardly influenced the sensitivity of P388/ADR cells to vinblastine (VLB), and cyclic disulfonamides with these aryl groups only slightly increased the sensitivity to VLB. Acyclic or cyclic disulfonamides with 4-chlorophenyl or naphthyl groups moderately potentiated the effect of VLB. The maximum effect was observed with 1, 5-bis(1-naphthale-nesulfonyl)-1, 3, 5-triazacycloheptan (B3). B3 enhanced the effects of vincristine, adriamycin, daunomycin and actinomycin D in P388/ADR cells, but not in sensitive P388 cells. B3 increased intracellular concentrations of VLB and adriamycin in P388/ADR cells. The expression of P-gp in P388/ADR cells was not affected by cultivation with B3 for 72 hours. These results indicated that the anti-multidrug resistance activities of B3 were dependent on its inhibitory effect on P-gp.