ABSTRACT
Several procedures based on the shake-flask method and designed to require a minimum amount of drug for octanol-water partition coefficient determination have been established and developed. The procedures have been validated by a 28 substance set with a lipophilicity range from -2.0 to 4.5 (logD7.4). The experimental partition is carried out using aqueous phases buffered with phosphate (pH 7.4) and n-octanol saturated with buffered water and the analysis is performed by liquid chromatography. In order to have accurate results, four procedures and eight different ratios between phase volumes are proposed. Each procedure has been designed and optimized (for partition ratios) for a specific range of drug lipophilicity (low, regular and high lipophilicity) and solubility (high and low aqueous solubility). The procedures have been developed to minimize the measurement in the octanolic phase. Experimental logD7.4 values obtained from different procedures and partition ratios show a standard deviation lower than 0.3 and there is a nice agreement when these values are compared with the reference literature ones.
Subject(s)
1-Octanol/chemistry , Chromatography, Liquid , Drug Discovery , Pharmaceutical Preparations/analysis , Solvents/chemistry , Technology, Pharmaceutical/methods , Water/chemistry , Buffers , Dimethyl Sulfoxide/chemistry , Hydrogen-Ion Concentration , Hydrophobic and Hydrophilic Interactions , Reproducibility of Results , SolubilityABSTRACT
A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H(1) antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT(2) receptor. Extensive optimization was carried out within this series and a number of histamine H(1) antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48,51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation.
Subject(s)
Histamine H1 Antagonists/chemical synthesis , Indoles/chemical synthesis , Piperidines/chemical synthesis , Animals , Blood-Brain Barrier/metabolism , Brain/metabolism , Capillary Permeability/drug effects , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Electrocardiography/drug effects , Guinea Pigs , Half-Life , Histamine H1 Antagonists/pharmacology , Histamine H1 Antagonists/toxicity , Humans , In Vitro Techniques , Indoles/pharmacology , Indoles/toxicity , Male , Mice , Piperidines/pharmacology , Piperidines/toxicity , Radioligand Assay , Rats , Rats, Wistar , Receptors, Adrenergic, alpha-1/drug effects , Receptors, Adrenergic, alpha-1/metabolism , Receptors, Histamine H1/drug effects , Receptors, Histamine H1/metabolism , Receptors, Serotonin/drug effects , Receptors, Serotonin/metabolism , Skin/blood supply , Structure-Activity RelationshipABSTRACT
A novel series of aminopyridine N-oxides were designed, synthesized, and tested for their ability to inhibit p38alpha MAP kinase. Some of these compounds showed a significant reduction in the LPS-induced TNFalpha production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for a marked selectivity against other related kinases. Compound 45 was identified as a potent and selective p38alpha inhibitor with an appropriate balance between potency and pharmacokinetics. In vivo efficacy of 45 was demonstrated in reducing TNFalpha levels in an acute murine model of inflammation (ED(50) = 1 mg/kg in LPS-induced TNFalpha production when dosed orally 1.5 h prior to LPS administration). The oral efficacy of 45 was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) = 4.5 mg/kg).
Subject(s)
Aminopyridines/chemistry , Aminopyridines/pharmacology , Drug Design , Oxides/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Aminopyridines/chemical synthesis , Aminopyridines/therapeutic use , Animals , Arthritis, Experimental/blood , Arthritis, Experimental/drug therapy , Catalytic Domain , Cell Line , Humans , Inhibitory Concentration 50 , Male , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/therapeutic use , Rats , Rats, Wistar , Structure-Activity Relationship , Substrate Specificity , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/blood , p38 Mitogen-Activated Protein Kinases/chemistryABSTRACT
The objective of this work was to discover a novel, long-acting muscarinic M(3) antagonist for the inhaled treatment of chronic obstructive pulmonary disease (COPD), with a potentially improved risk-benefit profile compared with current antimuscarinic agents. A series of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters were synthesized and evaluated. On the basis of its overall profile, (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) emerged as a candidate for once-daily maintenance treatment of COPD. This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. Aclidinium bromide is currently in phase III development for maintenance treatment of patients with COPD.