Chromatoprobe as a sample-sparing technique for residual solvent analysis of drug discovery candidates by gas chromatography.

In drug discovery research, residual solvent measurement is an integral part of purity analysis for synthesis of a drug candidate before it is used for toxicity testing. This is usually carried out using gas chromatography (GC) with direct injection sample introduction. This method requires testing compounds to be soluble at high concentrations (>50 mg/mL, usually in DMSO) to achieve acceptable sensitivity, a hurdle which is not always achievable for some samples such as cyclic peptides and oligonucleotides.

Tiered analytics for purity assessment of macrocyclic peptides in drug discovery: Analytical consideration and method development.

Synthetic macrocyclic peptides with natural and unnatural amino acids have gained considerable attention from a number of pharmaceutical/biopharmaceutical companies in recent years as a promising approach to drug discovery, particularly for targets involving protein-protein or protein-peptide interactions. Analytical scientists charged with characterizing these leads face multiple challenges including dealing with a class of complex molecules with the potential for multiple isomers and variable charge states and no established standards for acceptable analytical characterization of materials used in drug discovery. In addition, due to the lack of intermediate purification during solid phase peptide synthesis, the final products usually contain a complex profile of impurities.

AlMe(3)-promoted formation of amides from acids and amines.

In the presence of AlMe(3), amines can be directly coupled with acids through dimethylaluminum amide intermediates to form the corresponding amides. A wide range of amines and acids including less nucleophilic amines, bulky amines, unprotected secondary amino acids, and acids with poor solubility were coupled smoothly to give the desired products in 55-98% yields.

Chiral separation of potent corticotropin-releasing factor-1 receptor antagonists by supercritical fluid chromatography.

Pyrazinones bearing an N-1-alkyl chain with a chiral center have been reported as potent antagonists of the corticotropin-releasing factor-1 receptor (CRF1R). Separation of individual enantiomers for preclinical testing was an important aspect of lead optimization. To evaluate the applicability and efficiency of supercritical fluid chromatography (SFC) for enantiomeric resolution of this class of compounds, enantiomeric pairs of eight pyrazinones with different structural characteristics were tested under an array of SFC conditions.

A strategy to minimize reactive metabolite formation: discovery of (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-[6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino]-5-oxo-4,5-dihydropyrazine-2-carbonitrile as a potent, orally bioavailable corticotropin-releasing factor-1 receptor antagonist.

Detailed metabolic characterization of 8, an earlier lead pyrazinone-based corticotropin-releasing factor-1 (CRF(1)) receptor antagonist, revealed that this compound formed significant levels of reactive metabolites, as measured by in vivo and in vitro biotransformation studies. This was of particular concern due to the body of evidence suggesting that reactive metabolites may be involved in idiosyncratic drug reactions. Further optimization of the structure-activity relationships and in vivo properties of pyrazinone-based CRF(1) receptor antagonists and studies to assess the formation of reactive metabolites led to the discovery of 19e, a high affinity CRF(1) receptor antagonist (IC(50) = 0.

Synthesis, structure-activity relationships, and in vivo evaluation of N3-phenylpyrazinones as novel corticotropin-releasing factor-1 (CRF1) receptor antagonists.

Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.

Separation of maxi-K channel opening 3-substituted-4-arylquinolinone atropisomers by enantioselective supercritical fluid chromatography.

Many 3-substituted-4-arylquinolinones containing an ortho substituent on the aryl ring were known as a class of compounds with maxi-K opening activity. These quinolinones, which contained a stereogenic axis in their structures due to their bulky ortho substituents on the two aryl rings, exhibited atropisomerism. The rotationally hindered atropisomers could have differential biological and pharmacological activity, and it was highly desirable to separate them and test the individual atropisomers in biological assays.

Conformationally restricted homotryptamines 3. Indole tetrahydropyridines and cyclohexenylamines as selective serotonin reuptake inhibitors.

A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a.

Atropisomeric 3-(beta-hydroxyethyl)-4-arylquinolin-2-ones as Maxi-K potassium channel openers.

The synthesis of a series of 3-beta-hydroxyethyl-4-arylquinolin-2-ones is described. These compounds contain hydrophilic and hydrophobic substituents ortho to the phenolic OH in the C ring of the quinolinone. Electrophysiological evaluation of the panel of compounds revealed that 11 and 16 with an unbranched ortho substituent retain activity as maxi-K ion channel openers.

Stephacidin A and B: two structurally novel, selective inhibitors of the testosterone-dependent prostate LNCaP cells.

Two novel antitumor alkaloids, Stephacidin A and B, were isolated from the solid fermentation of Aspergillus ochraceus WC76466. Both alkaloids exhibit in vitro cytotoxicity against a number of human tumor cell lines; however, stephacidin B demonstrated more potent and selective antitumor activities, especially against prostate testeosterone-dependent LNCaP cells with IC50 value of 60 nM. The structures of stephacidin A and B were established on the basis of the NMR data and X-ray crystallography.