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1.
J Pharm Biomed Anal ; 138: 166-174, 2017 May 10.
Article in English | MEDLINE | ID: mdl-28213177

ABSTRACT

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. In this paper, practical analytical strategies and methodologies were developed to address these challenges, including a tiered approach to assessing the purity of macrocyclic peptides at different stages of drug discovery. Our results also showed that successful progression and characterization of a new drug discovery modality benefited from active analytical engagement, focusing on fit-for-purpose analyses and leveraging a broad palette of analytical technologies and resources.


Subject(s)
Chromatography, High Pressure Liquid/methods , Drug Discovery/methods , Magnetic Resonance Imaging/methods , Peptides/chemistry , Amino Acids/chemistry
2.
Org Lett ; 14(1): 214-7, 2012 Jan 06.
Article in English | MEDLINE | ID: mdl-22148911

ABSTRACT

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.


Subject(s)
Acids/chemistry , Aluminum/chemistry , Amides/chemical synthesis , Amines/chemistry , Organometallic Compounds/chemistry , Molecular Structure
3.
J Pharm Biomed Anal ; 54(3): 602-6, 2011 Feb 20.
Article in English | MEDLINE | ID: mdl-21036503

ABSTRACT

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. The results showed that pyrazinones with a 1-cyclopropyl-2-methoxyethyl substituent were readily separated with a Chiralpak AD-H or Chiralcel OD-H column with ethanol as the modifier. On the other hand, analogs with a less polar alkyl substituent were not amenable to the general method and required further optimization of the chromatographic conditions. In addition, structural variations on the pyrazinone core and aromatic moiety had an impact on the chiral resolution of this class of compounds. This investigation led to the development of efficient chiral SFC methods for separating all eight pyrazinone enantiomeric pairs encompassing an array of structural variations.


Subject(s)
Chromatography, Supercritical Fluid , Pyrazines/isolation & purification , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Amylose/analogs & derivatives , Corticotropin-Releasing Hormone/metabolism , Humans , Phenylcarbamates , Pyrazines/analysis , Receptors, Corticotropin-Releasing Hormone/metabolism , Stereoisomerism
4.
J Med Chem ; 52(23): 7653-68, 2009 Dec 10.
Article in English | MEDLINE | ID: mdl-19954247

ABSTRACT

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) = 0.86 nM) wherein GSH adducts were estimated to be only 0.1% of the total amount of drug-related material excreted through bile and urine, indicating low levels of reactive metabolite formation in vivo. A novel 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group in 19e contributed to the potency and improved in vivo properties of this compound and related analogues. 19e had excellent pharmacokinetic properties in rats and dogs and showed efficacy in the defensive withdrawal model of anxiety in rats. The lowest efficacious dose was 1.8 mg/kg. The results of a two-week rat safety study with 19e indicated that this compound was well-tolerated.


Subject(s)
Pyrazines/metabolism , Pyrazines/pharmacology , Pyridines/metabolism , Pyridines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Dogs , Drug Discovery , Drug Stability , Humans , Male , Pyrazines/administration & dosage , Pyrazines/pharmacokinetics , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Rats
5.
J Med Chem ; 52(14): 4173-91, 2009 Jul 23.
Article in English | MEDLINE | ID: mdl-19552437

ABSTRACT

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 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described.


Subject(s)
Pyrazines/chemistry , Pyrazines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Cell Line, Tumor , Humans , Macaca fascicularis , Male , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
6.
J Pharm Biomed Anal ; 48(4): 1120-6, 2008 Dec 01.
Article in English | MEDLINE | ID: mdl-18922657

ABSTRACT

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. To explore the potential of supercritical fluid chromatography (SFC) to separate the atropisomers of this class of compounds, six 3-substituted-4-arylquinolinones with various hydrophilic and hydrophobic substituents in various positions were screened using three alcoholic modifiers (methanol, ethanol and 2-propanol) with four polysaccharide-based chiral stationary phases (Chiralpak AD-H and AS-H, Chiralcel OD-H and OJ-H). Our results showed that all six compounds studied were successfully resolved under multiple SFC conditions regardless of their structural differences and polarity. The majority of the separations were completed within 10 min. The Chiralpak AD-H column appeared to be superior to the other three chiral columns, and methanol and ethanol showed higher successful rate than 2-propanol in separating atropisomers of this class of compounds. These SFC methods were efficient and easily scalable for preparative separation. Thus, SFC was found to be the methodology of choice for resolving the atropisomers of this class of compounds.


Subject(s)
Chromatography, Supercritical Fluid/methods , Large-Conductance Calcium-Activated Potassium Channels/isolation & purification , Quinolones/isolation & purification , Alcohols/chemistry , Drug Design , Large-Conductance Calcium-Activated Potassium Channels/chemistry , Molecular Structure , Quinolones/chemistry , Stereoisomerism , Temperature , Time Factors
7.
Bioorg Med Chem Lett ; 17(11): 3099-104, 2007 Jun 01.
Article in English | MEDLINE | ID: mdl-17391962

ABSTRACT

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. The enantiomers of 6a were energy minimized and compared to other conformationally restricted SSRIs. Compound 6a was found to give a dose-response similar to the SSRI fluoxetine in microdialysis studies in rats.


Subject(s)
Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Tryptamines/chemistry , Animals , Cyclohexenes/chemical synthesis , Cyclohexenes/chemistry , Cyclohexenes/pharmacology , Fluoxetine/chemistry , Fluoxetine/pharmacology , Humans , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Microdialysis , Molecular Conformation , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Rats , Selective Serotonin Reuptake Inhibitors/chemical synthesis
8.
J Med Chem ; 50(5): 1050-7, 2007 Mar 08.
Article in English | MEDLINE | ID: mdl-17274609

ABSTRACT

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. Members of this series of compounds can exist as stable atropisomers. Calculated estimates of the energy barrier for rotation around the aryl-aryl single bond in 3 is 31 kcal/mol. The atropisomers of (+/-)-3, (+/-)-4, and (+/-)-11 were separated by chiral HPLC and tested for their effect on maxi-K mediated outward current in hSlo injected X. laevis oocytes. The (-) isomer in each case was found to be more active than the corresponding (+) isomer, suggesting that the ion channel exhibits stereoselective activation. X-ray crystallographic structures of (+)-3 and (+)-11 were determined. Evaluation of the stability of (-)-3 at 80 degrees C in n-butanol indicated a 19.6% conversion to (+)-3 over 72 h. In human serum at 37 degrees C (-)-3 did not racemize over the course of the 30 h study.


Subject(s)
Large-Conductance Calcium-Activated Potassium Channels/drug effects , Quinolines/chemical synthesis , Animals , Crystallography, X-Ray , Female , Humans , In Vitro Techniques , Ion Channel Gating , Large-Conductance Calcium-Activated Potassium Channels/physiology , Molecular Structure , Oocytes/drug effects , Oocytes/physiology , Patch-Clamp Techniques , Quinolines/chemistry , Quinolines/pharmacology , Stereoisomerism , Thermodynamics , Xenopus laevis
9.
J Am Chem Soc ; 124(49): 14556-7, 2002 Dec 11.
Article in English | MEDLINE | ID: mdl-12465964

ABSTRACT

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. With 15 rings and 9 chiral centers, stephacidin B represents one of the most structurally complex and novel alkaloids occurring in nature.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aspergillus ochraceus/chemistry , Indoles/chemistry , Indoles/isolation & purification , Neoplasms, Hormone-Dependent/drug therapy , Prostatic Neoplasms/drug therapy , Antineoplastic Agents/isolation & purification , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Indole Alkaloids , Indoles/pharmacology , Male , Molecular Structure , Neoplasms, Hormone-Dependent/pathology , Nuclear Magnetic Resonance, Biomolecular , Prostatic Neoplasms/pathology , Testosterone/physiology , Tumor Cells, Cultured
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