No abstract

This study examined the pharmacologic characterization of CHF6001 [(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) phenyl)-2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)ethyl)pyridine 1-oxide], a novel phosphodiesterase (PDE) 4 inhibitor designed for treating pulmonary inflammatory diseases via inhaled administration. CHF6001 was 7-and 923-fold more potent than roflumilast and cilomilast, respectively, in inhibiting PDE4 enzymatic activity (IC 50 5 0.026 6 0.006 nM). CHF6001 inhibited PDE4 isoforms A-D with equal potency, showed an elevated ratio of high-affinity rolipram binding site versus low-affinity rolipram binding site (i.e., .40) and displayed .20,000-fold selectivity versus PDE4 compared with a panel of PDEs. CHF6001 effectively inhibited (subnanomolar IC 50 values) the release of tumor necrosis factor-a from human peripheral blood mononuclear cells, human acute monocytic leukemia cell line macrophages (THP-1), and rodent macrophages (RAW264.7 and NR8383). Moreover, CHF6001 potently inhibited the activation of oxidative burst in neutrophils and eosinophils, neutrophil chemotaxis, and the release of interferon-g from CD4 1 T cells. In all these functional assays, CHF6001 was more potent than previously described PDE4 inhibitors, including roflumilast, UK-500,001 [2-(3,4-difluorophenoxy)-5-fluoro-N-((1S,4S)-4-(2-hydroxy-5-methylbenzamido)cyclohexyl)nicotinamide], and cilomilast, and it was comparable to GSK256066 [6-((3-(dimethylcarbamoyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide]. When administered intratracheally to rats as a micronized dry powder, CHF6001 inhibited liposaccharide-induced pulmonary neutrophilia (ED 50 5 0.205 mmol/kg) and leukocyte infiltration (ED 50 5 0.188 mmol/kg) with an efficacy comparable to a high dose of budesonide (1 mmol/kg i. p.). In sum, CHF6001 has the potential to be an effective topical treatment of conditions associated with pulmonary inflammation, including asthma and chronic obstructive pulmonary disease.

Some members of the title compounds such as the calixcrown (Ia) or the calixspherand (Ib) are prepared by common methods and the kinetic and thermodynamic stabilities of their alkali cation complexes are measured.

No abstract

The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.

No abstract

Ganstigmine is an orally active, geneserine derived, carbamate-based acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The crystal structure of the ganstigmine conjugate with Torpedo californica acetylcholinesterase (TcAChE) has been determined at 2.40 A resolution, and a detailed structure-based analysis of the in vitro and ex vivo anti-AChE activity by ganstigmine and by new geneserine derivatives is presented. The carbamoyl moiety is covalently bound to the active-site serine, whereas the leaving group geneseroline is not retained in the catalytic pocket. The nitrogen atom of the carbamoyl moiety of ganstigmine is engaged in a key hydrogen-bonding interaction with the active site histidine (His440). This result offers an explanation for the inactivation of the catalytic triad and may account for the long duration of action of ganstigmine in vivo. The 3D structure also provides a structural framework for the design of compounds with improved binding affinity and pharmacological properties.

Three different conformers of 1,3-diethoxy-p-tert-butylcalix [4] arene crown ethers have been used to study the effect of the ionophore preorganization on the potentiometric K + -selectivity. Selectivities were measured for chemically modified field effect transistors (CH EM FETs) and membrane ion-selective electrodes (ISEs) by two different methods. The ionophores show decreasing K + / N a + selectivities in the order: partial cone > 1.3-alternate > cone. As a function of time the cone conformer maintained a constant selectivity whereas a continuous decrease of the selectivity values was observed for the other two conformers. This supports our prediction based on the association constants and our previous 'H N MR studies on conformational stability.