ABSTRACT
An electrospinning process was optimized to produce fibers of micrometric size with different combinations of polymeric and surfactant materials to promote the dissolution rate of an insoluble drug: firocoxib. Scanning Electron Microscopy (SEM) showed that only some combinations of the proposed carrier systems allowed the production of suitable fibers and further fine optimization of the technique is also needed to load the drug. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) suggest that the drug is in an amorphous state in the final product. Drug amorphization, the fine dispersion of the active in the carriers, and the large surface area exposed to water interaction obtained through the electrospinning process can explain the remarkable improvement in the dissolution performance of firocoxib from the final product developed.
Subject(s)
4-Butyrolactone/analogs & derivatives , Cyclooxygenase 2 Inhibitors/administration & dosage , Cyclooxygenase 2 Inhibitors/chemistry , Drug Carriers , Nanofibers , Polymers , Sulfones/administration & dosage , Sulfones/chemistry , Surface-Active Agents , 4-Butyrolactone/administration & dosage , 4-Butyrolactone/chemistry , Drug Carriers/chemistry , Nanofibers/chemistry , Nanofibers/ultrastructure , Polymers/chemistry , Solubility , Spectroscopy, Fourier Transform Infrared , Surface-Active Agents/chemistry , ThermodynamicsABSTRACT
High-throughput screening resulted in the identification of a series of novel motilin receptor agonists with relatively low molecular weights. The series originated from an array of biphenyl derivatives designed to target 7-transmembrane (7-TM) receptors. Further investigation of the structure-activity relationship within the series resulted in the identification of compound (22) as a potent and selective agonist at the motilin receptor.
Subject(s)
Receptors, Gastrointestinal Hormone/agonists , Receptors, Gastrointestinal Hormone/chemistry , Receptors, Neuropeptide/agonists , Receptors, Neuropeptide/chemistry , Animals , Binding Sites , Cell Membrane/metabolism , Chemistry, Pharmaceutical/methods , Combinatorial Chemistry Techniques , Drug Design , Drug Evaluation, Preclinical , Humans , Models, Chemical , Molecular Structure , Receptors, G-Protein-Coupled/metabolism , Recombinant Proteins/chemistry , Structure-Activity RelationshipABSTRACT
Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.
Subject(s)
Carbon/chemistry , Pyridines/chemistry , Receptors, Gastrointestinal Hormone/agonists , Receptors, Neuropeptide/agonists , Animals , Chemistry, Pharmaceutical/methods , Drug Design , Gastrins/chemistry , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Pyridines/chemical synthesis , Pyridines/pharmacology , Rabbits , Rats , Receptors, Gastrointestinal Hormone/chemistry , Receptors, Neuropeptide/chemistryABSTRACT
The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The introduction of a tricyclic [h]-fused benzazepine moiety on the recently disclosed scaffold of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines is reported. A full rat pharmacokinetic characterization is also reported.
Subject(s)
Benzazepines/chemical synthesis , Benzazepines/pharmacology , Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Benzazepines/chemistry , Combinatorial Chemistry Techniques , Dopamine Antagonists/chemistry , Drug Design , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
trans-6-Aminocyclohept-3-enols 18 and ent-18 are new designed polyfunctionalized chiral building blocks for piperidine alkaloids synthesis and are prepared in high yields from the enzymatically derived cyclohept-3-ene-1,6-diol monoacetate (-)-8. Efficient highly enantioselective syntheses of cis-4-hydroxypipecolic acid (1) and piperidines 3 and 4, in both enantiomeric forms, are described. [reaction: see text]
