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1.
ChemSusChem ; 17(1): e202300964, 2024 Jan 08.
Article in English | MEDLINE | ID: mdl-37696772

ABSTRACT

Transition metal-catalyzed, non-enzymatic nitrene transfer (NT) reactions to selectively transform C-H and C=C bonds to new C-N bonds are a powerful strategy to streamline the preparation of valuable amine building blocks. However, many catalysts for these reactions use environmentally unfriendly solvents that include dichloromethane, chloroform, 1,2-dichloroethane and benzene. We developed a high-throughput experimentation (HTE) protocol for heterogeneous NT reaction mixtures to enable rapid screening of a broad range of solvents for this chemistry. Coupled with the American Chemical Society Pharmaceutical Roundtable (ACSPR) solvent tool, we identified several attractive replacements for chlorinated solvents. Selected catalysts for NT were compared and contrasted using our HTE protocol, including silver supported by N-dentate ligands, dinuclear Rh complexes and Fe/Mn phthalocyanine catalysts.

2.
ACS Med Chem Lett ; 14(4): 514-520, 2023 Apr 13.
Article in English | MEDLINE | ID: mdl-37077398

ABSTRACT

Chemical- and enzyme-coated beads (ChemBeads and EnzyBeads) were introduced recently as a universal strategy for the accurate dispensing of various solids in submilligram quantities using automated instrumentation or manual dispensing. The coated beads are prepared using a resonant acoustic mixer (RAM)-an instrument that may be available only to well-established facilities. In this study, we evaluated alternative coating methods for preparing ChemBeads and EnzyBeads without the use of a RAM. We also evaluated the effects of bead sizes on loading accuracy using 4 coating methods and 12 solids (9 chemicals and 3 enzymes) as test subjects. While our original RAM coating method is the most versatile for the broadest range of solids, high-quality ChemBeads and EnzyBeads that are suitable for high-throughput experimentation can be prepared using alternative methods. These results should make ChemBeads and EnzyBeads readily accessible as the core technology for setting up high-throughput experimentation platforms.

3.
ACS Med Chem Lett ; 14(4): 521-529, 2023 Apr 13.
Article in English | MEDLINE | ID: mdl-37077401

ABSTRACT

Enthusiasm surrounding nickel/photoredox C(sp2)-C(sp3) cross-couplings is very high; however, these methods are sometimes challenged by complex drug-like substrates in discovery chemistry. In our hands this has been especially true of the decarboxylative coupling, which has lagged behind other photoredox couplings in internal adoption and success. Herein, the development of a photoredox high-throughput experimentation platform to optimize challenging C(sp2)-C(sp3) decarboxylative couplings is described. Chemical-coated glass beads (ChemBeads) and a novel parallel bead dispenser are used to expedite the high-throughput experimentation process and identify improved coupling conditions. In this report, photoredox high-throughput experimentation is utilized to dramatically improve low-yielding decarboxylative C(sp2)-C(sp3) couplings, and libraries, using conditions not previously identified in the literature.

4.
Angew Chem Int Ed Engl ; 58(24): 7987-7991, 2019 06 11.
Article in English | MEDLINE | ID: mdl-30891860

ABSTRACT

Technologies that enable rapid screening of diverse reaction conditions are of critical importance to methodology development and reaction optimization, especially when molecules of high complexity and scarcity are involved. The lack of a general solid dispensing method for chemical reagents on micro- and nanomole scale prevents the full utilization of reaction screening technologies. We herein report the development of a technology in which glass beads coated with solid chemical reagents (ChemBeads) enable the delivery of nanomole quantities of solid chemical reagents efficiently. By exploring the concept of preferred screening sets, the flexibility and generality of this technology for high-throughput reaction screening was validated.

5.
Bioorg Med Chem Lett ; 27(15): 3317-3325, 2017 08 01.
Article in English | MEDLINE | ID: mdl-28610984

ABSTRACT

Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cytokines/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors , Urea/analogs & derivatives , Urea/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Cytokines/chemistry , Cytokines/metabolism , Drug Discovery , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Humans , Isoindoles/chemistry , Isoindoles/pharmacokinetics , Isoindoles/pharmacology , Isoindoles/therapeutic use , Mice , Models, Molecular , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Nicotinamide Phosphoribosyltransferase/chemistry , Nicotinamide Phosphoribosyltransferase/metabolism , Structure-Activity Relationship , Urea/pharmacokinetics , Urea/therapeutic use
6.
ACS Med Chem Lett ; 8(4): 461-465, 2017 Apr 13.
Article in English | MEDLINE | ID: mdl-28435537

ABSTRACT

The productivity of medicinal chemistry programs can be significantly increased through the introduction of automation, leading to shortened discovery cycle times. Herein, we describe a platform that consolidates synthesis, purification, quantitation, dissolution, and testing of small molecule libraries. The system was validated through the synthesis and testing of two libraries of binders of polycomb protein EED, and excellent correlation of obtained data with results generated through conventional approaches was observed. The fully automated and integrated platform enables batch-supported compound synthesis based on a broad array of chemical transformations with testing in a variety of biochemical assay formats. A library turnaround time of between 24 and 36 h was achieved, and notably, each library synthesis produces sufficient amounts of compounds for further evaluation in secondary assays thereby contributing significantly to the shortening of medicinal chemistry discovery cycles.

7.
J Lab Autom ; 21(3): 459-69, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26085482

ABSTRACT

A novel methodology for the synthesis and purification of drug-like compound libraries has been developed through the use of a microwave reactor with an integrated high-performance liquid chromatography-mass spectrometry (HPLC-MS) system. The strategy uses a fully automated synthesizer with a microwave as energy source and robotic components for weighing and dispensing of solid reagents, handling liquid reagents, capper/crimper of microwave reaction tube assemblies, and transportation. Crude reaction products were filtered through solid-phase extraction cartridges and injected directly onto a reverse-phase chromatography column via an injection valve. For multistep synthesis, crude products were passed through scavenger resins and reintroduced for subsequent reactions. All synthetic and purification steps were conducted under full automation with no handling or isolation of intermediates, to afford the desired purified products. This approach opens the way to highly efficient generation of drug-like compounds as part of a lead discovery strategy or within a lead optimization program.


Subject(s)
Automation, Laboratory/methods , Microwaves , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/isolation & purification , Chromatography, Liquid/methods , Mass Spectrometry/methods
8.
J Lab Autom ; 19(2): 176-82, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24352687

ABSTRACT

A flexible and integrated flow-chemistry-synthesis-purification compound-generation and sample-management platform has been developed to accelerate the production of small-molecule organic-compound drug candidates in pharmaceutical research. Central to the integrated system is a Mitsubishi robot, which hands off samples throughout the process to the next station, including synthesis and purification, sample dispensing for purity and quantification analysis, dry-down, and aliquot generation.


Subject(s)
Combinatorial Chemistry Techniques/methods , Drug Discovery/methods , High-Throughput Screening Assays/methods , Organic Chemicals/isolation & purification , Organic Chemicals/pharmacology , Specimen Handling/methods , Organic Chemicals/chemical synthesis
9.
Mol Divers ; 16(1): 53-8, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21927797

ABSTRACT

We present a study on ultrasound-promoted click chemistry reactions in a meso-flow reactor synthesis system with a copper reactor and a custom sonication piezoelectric transducer. Copper catalyzed Huisgen 1,3-dipolar cycloadditions were studied in flow with this system. Our results demonstrate that 1,4-disubstituted 1,2,3-triazole products can be generated at low temperatures and with short reaction time in good yield, due to the rate enhancement effect of sonication.


Subject(s)
Click Chemistry/methods , Rheology , Ultrasonics/methods , Area Under Curve , Temperature , Transducers , Triazoles/chemical synthesis , Triazoles/chemistry
10.
Bioorg Med Chem Lett ; 20(8): 2443-7, 2010 Apr 15.
Article in English | MEDLINE | ID: mdl-20338758

ABSTRACT

A series of alkenyl indazoles were synthesized and evaluated in Aurora kinase enzyme assays. Several promising leads were optimized for selectivity towards Aurora B. Excellent binding affinity and good selectivity were achieved with optimized compounds in isolated Aurora subfamily assays.


Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Aurora Kinases , Drug Evaluation, Preclinical , Models, Molecular , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism
11.
J Chromatogr A ; 1216(19): 4154-60, 2009 May 08.
Article in English | MEDLINE | ID: mdl-19108843

ABSTRACT

Experiments were performed to evaluate whether counter-current chromatography (CCC) could function as an alternative purification method to reversed-phase high-performance liquid chromatography (RP-HPLC) and normal-phase supercritical fluid chromatography (SFC). RP-HPLC and SFC are the routine methods currently used in our high-throughput purification (HTP) facility for the purification of high-throughput organic synthesis (HTOS) libraries and medicinal chemistry reaction mixtures. Pre-equilibration of the solvent mixture layers was not mandatory for effective chromatography when hexanes-ethyl acetate-methanol-water (HEMW) solvent mixtures were used. Key to the use of CCC for high-throughput applications is the ability to effectively select a solvent system appropriate to each library member. Pilot-scale CCC elution time was used to estimate a starting solvent ratio and RP-HPLC retention time was then used to adjust solvent ratios within a particular library. It was also found that dimethyl sulfoxide (DMSO) and DMSO-methanol were suitable as sample injection solvents when using the HEMW solvent systems.


Subject(s)
Countercurrent Distribution/methods , Organic Chemicals/chemistry , Small Molecule Libraries , Acylation , Chromatography, High Pressure Liquid , Dimethyl Sulfoxide/chemistry , Equipment Design , Ibuprofen/isolation & purification , Ketoprofen/isolation & purification , Methanol/chemistry , Solubility , Solvents/chemistry
12.
J Comput Aided Mol Des ; 22(12): 897-906, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18574696

ABSTRACT

The Aurora family of serine/threonine kinases are mitotic regulators involved in centrosome duplication, formation of the bipolar mitotic spindle and the alignment of the chromosomes along the spindle. These proteins are frequently overexpressed in tumor cells as compared to normal cells and are therefore potential therapeutic oncology targets. An Aurora A high throughput screen revealed a promising sub-micromolar indazole-benzimidazole lead. Modification of the benzimidazole portion of the lead to a C2 linker with a phenyl ring was proposed to achieve novelty. Docking revealed that a conjugated linker was optimal and the resulting compounds were equipotent with the lead. Further structure-guided optimization of substituents on the 5 & 6 position of the indazole led to single digit nanomolar potency. The homology between the Aurora A & Aurora B kinase domains is 71% but their binding sites only differ at residues 212 & 217 (Aurora A numbering). However interactions with only the latter residue may be used for obtaining selectivity. An analysis of published Aurora A and Aurora B X-ray structures reveals subtle differences in the shape of the binding sites. This was exploited by introduction of appropriately sized substituents in the 4 & 6 position of the indazole leading to Aurora B selective inhibitors. Finally we calculate the conformational energy penalty of the putative bioactive conformation of our inhibitors and show that this property correlates well with the Aurora A binding affinity.


Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Aurora Kinases , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/pharmacology
14.
J Pharmacol Exp Ther ; 314(1): 191-200, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15784656

ABSTRACT

Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.


Subject(s)
Blood Glucose/metabolism , Cholic Acids/pharmacology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Estrone/analogs & derivatives , Glucose/metabolism , Liver/metabolism , Receptors, Glucocorticoid/antagonists & inhibitors , 3T3 Cells , Adipocytes/metabolism , Animals , Biotransformation/drug effects , Cell Differentiation/drug effects , Cholic Acids/metabolism , Diabetes Mellitus, Type 2/blood , Dogs , Drug Synergism , Estrone/metabolism , Estrone/pharmacology , Glucocorticoids/pharmacology , Glutamate-Ammonia Ligase/metabolism , Hypoglycemic Agents/pharmacology , Male , Mice , Obesity/metabolism , Prednisolone/pharmacology , Rats , Rats, Zucker , Reverse Transcriptase Polymerase Chain Reaction , Rosiglitazone , Thiazolidinediones/pharmacology , Tyrosine Transaminase/metabolism
15.
J Med Chem ; 47(17): 4213-30, 2004 Aug 12.
Article in English | MEDLINE | ID: mdl-15293993

ABSTRACT

Hepatic blockade of glucocorticoid receptors (GR) suppresses glucose production and thus decreases circulating glucose levels, but systemic glucocorticoid antagonism can produce adrenal insufficiency and other undesirable side effects. These hepatic and systemic responses might be dissected, leading to liver-selective pharmacology, when a GR antagonist is linked to a bile acid in an appropriate manner. Bile acid conjugation can be accomplished with a minimal loss of binding affinity for GR. The resultant conjugates remain potent in cell-based functional assays. A novel in vivo assay has been developed to simultaneously evaluate both hepatic and systemic GR blockade; this assay has been used to optimize the nature and site of the linker functionality, as well as the choice of the GR antagonist and the bile acid. This optimization led to the identification of A-348441, which reduces glucose levels and improves lipid profiles in an animal model of diabetes.


Subject(s)
Bridged-Ring Compounds/chemical synthesis , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/chemical synthesis , Liver/metabolism , Receptors, Glucocorticoid/antagonists & inhibitors , Animals , Bile Acids and Salts/chemistry , Binding Sites , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , CHO Cells , Cells, Cultured , Computer Simulation , Cricetinae , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Type 2/blood , Glucose/biosynthesis , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/physiology , Male , Mice , Models, Molecular , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/physiology , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/metabolism , Structure-Activity Relationship
16.
Bioorg Med Chem Lett ; 14(16): 4179-83, 2004 Aug 16.
Article in English | MEDLINE | ID: mdl-15261266

ABSTRACT

Bile acid conjugates of a selective nonsteroidal glucocorticoid receptor modulator were prepared and evaluated. Potent GR binding conjugates that showed improved metabolic stability were discovered. However, cellular potency and pharmacokinetics were not substantially improved.


Subject(s)
Bile Acids and Salts/chemistry , Receptors, Glucocorticoid/drug effects , Animals , Bile Acids and Salts/pharmacokinetics , Biological Availability , Rats , Rats, Sprague-Dawley
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