Solution Phase Synthesis Of Libraries Research Articles

Acyl Guanidine Inhibitors of β-Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution-Phase Library Synthesis

This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-π interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma Aβ levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain Aβ levels were not obtained.

Parallel medicinal chemistry approaches to selective HDAC1/HDAC2 inhibitor (SHI-1:2) optimization

The successful application of both solid and solution phase library synthesis, combined with tight integration into the medicinal chemistry effort, resulted in the efficient optimization of a novel structural series of selective HDAC1/HDAC2 inhibitors by the MRL-Boston Parallel Medicinal Chemistry group. An initial lead from a small parallel library was found to be potent and selective in biochemical assays. Advanced compounds were the culmination of iterative library design and possess excellent biochemical and cellular potency, as well as acceptable PK and efficacy in animal models.

Prospects for Combinatorial Chemistry in the Agrosciences

The recent progress and future prospects for the successful application of combinatorial chemistry and high throughput screening within the agrochemical lead discovery process are outlined and discussed. Solid and solution phase library synthesis technologies are reviewed and compared, and the role and importance of bioavailability, diversity and virtual screening in rational library design are detailed.

Pyrazole CCK 1 receptor antagonists. Part 1: Solution-phase library synthesis and determination of Free–Wilson additivity

High throughput screening revealed compound 1 as a potent antagonist of the CCK 1 receptor. Evaluation of the CCK 1 SAR in a series of these diarylpyrazole antagonists was conducted in a matrix synthesis format revealing additive (Free–Wilson) and non-additive SAR. This use of additive QSAR modeling in conjunction with combinatorial libraries represents a unique approach to the evaluation of SAR interactions between the variables of any combinatorial matrix.

Advancing Parallel Solution Phase Library Synthesis through Efficient Purification, Quantitation, and Characterization Techniques

Historically, access to large numbers of quality compounds in a parallel solution phase library synthesis environment has been hindered by the inability to rapidly purify, quantitate, and characterize solution phase libraries in an efficient and cost effective manner. At Neurogen Corporation, we overcome these barriers by employing a collection of novel workstations in the High Speed Synthesis (HSS) group that are tightly integrated into our informatics architecture. This approach supports rapid and reliable instrument operation, rapid interpretation of results, and decision analysis for further downstream tasks and processing. Our movement of library samples and data from workstation to workstation facilitates synthesis throughput and the utilization of equipment, creating a cost-effective library production environment.

Advancing Parallel Solution Phase Library Synthesis through Efficient Purification, Quantitation, and Characterization Techniques

Historically, access to large numbers of quality compounds in a parallel solution phase library synthesis environment has been hindered by the inability to rapidly purify, quantitate, and characterize solution phase libraries in an efficient and cost effective manner. At Neurogen Corporation, we overcome these barriers by employing a collection of novel workstations in the High Speed Synthesis (HSS) group that are tightly integrated into our informatics architecture. This approach supports rapid and reliable instrument operation, rapid interpretation of results, and decision analysis for further downstream tasks and processing. Our movement of library samples and data from workstation to workstation facilitates synthesis throughput and the utilization of equipment, creating a cost-effective library production environment.

Polymer-assisted solution-phase library synthesis and crystal structure of alpha-ketothiazoles as tissue factor VIIa inhibitors.

A solution-phase synthesis of an alpha-ketothiazole library of the general form D-Phe-L-AA-Arg-alpha-ketothiazole is described. The five-step synthesis is accomplished using a combination of polymeric reagents and polymer-assisted solution-phase purification concepts, including reactant-sequestering resins, reagent-sequestering resins, and tagged reagents. The multistep synthesis affords desired alpha-ketothiazole products in excellent purities and yields. A variety of L-amino acid inputs were used to probe the S2 pocket of tissue Factor VIIa enzyme to influence both potency and selectivity. An X-ray crystal structure of compound 10k bound to the TF/VIIa complex was obtained that explains the observed selectivity. The alpha-ketothiazoles were found to be potent, reversible-covalent inhibitors of tissue Factor VIIa, with some analogues demonstrating selectivity over thrombin.

Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex.

Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of pyrazinone inhibitors of the tissue factor/Factor VIIa complex. The crystal structure of a tri-peptide ketothiazole complexed with TF/VIIa was utilized in a docking experiment that identified a benzyl-substituted pyrazinone as a P(2) surrogate for the tri-peptide. A 5-step PASP library synthesis of these aryl-substituted pyrazinones was developed. The sequence allows for attachment of a variety of P(1) and P(3) moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC(50) against TF/VIIa with >6250x selectivity versus Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for pre-clinical intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a primate model of thrombosis.

The annual analysis of the power output and heat gain of a PV-wall with different integration mode in Hong Kong : Jie, J. et al. Solar Energy Materials and Solar Cells, 2002, 71, (4), 435–448

Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of pyrazinone inhibitors of the tissue factor/Factor VIIa complex. The crystal structure of a tri-peptide ketothiazole complexed with TF/VIIa was utilized in a docking experiment that identified a benzyl-substituted pyrazinone as a P2 surrogate for the tri-peptide. A 5-step PASP library synthesis of these aryl-substituted pyrazinones was developed. The sequence allows for attachment of a variety of P1 and P3 moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC50 against TF/VIIa with >6250× selectivity versus Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for pre-clinical intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a primate model of thrombosis.

Ceric Ammonium Nitrate (CAN) Catalyzed Ring Cleavage of N‐Tosyl Aziridines: A Potential Tool for Solution Phase Library Generation.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Ceric ammonium nitrate (CAN) catalyzed ring cleavage of N-tosyl aziridines: a potential tool for solution phase library generation

A range of N-tosylaziridines is cleaved with NaN 3, H 2O, MeOH to synthesize vicinal azidoamines, aminols and amino ethers in good to excellent yields catalyzed by ceric ammonium nitrate and used in solution phase library synthesis.

Discovery of potent and selective phenylalanine derived CCR3 antagonists. Part 1

The discovery of a series of phenylalanine derived CCR3 antagonists is reported. Parallel, solution-phase library synthesis has been utilized to delineate the structure–activity relationship leading to the synthesis of highly potent, CCR3-selective antagonists.

Polymer-assisted solution-phase library synthesis of 4-alkoxy-2-hydroxy-3,5,6-trifluorobenzoic acids

The efficient synthesis of a small library of 4-alkoxy-2-hydroxy-3,5,6-trifluorobenzoic acids is described via the fluoride mediated alkylation of 5,6,8-trifluoro-7-hydroxy-2-methyl-benzo[1,3]dioxin-4-one with a collection of structurally diverse bromoalkanes. The use of ion-exchange resins during the reaction sequence enabled the preparation of the majority of the products in 82–98% purity without the need for chromatography.

Solution Phase Synthesis of Libraries of Variably Substituted Olefin Scaffolds: A Library of Allylic Amines

The synthesis of allylic amine libraries derived from olefin templates is described. The two-step, solution phase reaction sequence consists of amination of the template followed by Suzuki coupling and expedited purification via ion exchange chromatography. The methodology has been used to synthesize a 1344-member allylic amine library.

Solution phase synthesis of libraries of polycyclic natural product analogues by cascade radical annulation: synthesis of a 64-member library of mappicine analogues and a 48-member library of mappicine ketone analogues.

An improved cascade radical annulation route to (+/-)-mappicine, (S)-mappicine, and mappicine ketone is reported. The route is used to prepare libraries of mappicine and mappicine ketone analogues in a semiautomated fashion. Key diversity generating steps include the addition of an aldehyde to a Grignard reagent derived from a D-ring iodopyridine, N-propargylation of a subsequently derived iodopyridone, and cascade radical annulation with an isonitrile to form a mappicine analogue. Parallel oxidation of mappicine analogues produced mappicine ketones. The route is general and flexible and could be used to make very large libraries. It is also illustrative of how late stage cascade reactions can be employed strategically to generate libraries of polycyclic natural product analogues.

Multi-step polymer-assisted solution-phase (PASP) library synthesis of functionalized diaminobenzamides.

A parallel solution-phase library synthesis of functionalized diaminobenzamides is described. The four-step library synthesis is accomplished using polymer-assisted solution-phase (PASP) synthesis techniques. This high-yielding, multi-step sequence utilizes sequestering resins for the removal of reactants, reactant by-products, and employs a resin capture/release strategy as a key library synthesis step. Step one of the sequence relies on the displacement of an activated fluoro-group from the aromatic ring of 1a, b with a variety of primary amines to introduce the first diversity position. Step two is hydrolysis of the benzoate ester to a benzoic acid which is subsequently captured on a polyamine resin, washed, and released to give 4a, b in pure form. Step three utilizes PASP resins to mediate the amide coupling of a benzoic acid with a variety of primary amines to give the aminonitrobenzamides 5a, b and introduces the second diversity position. Step four is the parallel reduction of the aminonitrobenzamides 5a, b to the functionalized diaminobenzamides 6a, b. This library synthesis proceeds with high overall purities which average 80 % over the 4-step sequence.

Polymer-assisted solution-phase (PASP) library synthesis of alpha-ketoamides.

A parallel solution-phase library synthesis of alpha-ketoamides is described. The two-step library synthesis is accomplished using polymer-assisted solution-phase (PASP) synthesis techniques. This high-yielding, multi-step sequence utilizes sequestering resins for the removal of reactants, reactant by-products, and tagged reagents. The first step of the library synthesis utilizes PASP resins to mediate the amide coupling of an alpha-hydroxy acid with an amine. The second step uses PASP resins for the periodinane oxidation of the alpha-hydroxy acid to an alpha-ketoamide leaving highly pure products after simple filtration and evaporation.

Amidine protection for solution phase library synthesis

The application of 4-methoxybenzyl-4-nitrophenylcarbonate as a reagent for the N-protection of amidinonaphthol has been demonstrated. The facile introduction of the 4-methoxybenzyloxycarbonyl group and the mildness of the deprotection conditions make this reagent well suited for the multiparallel solution phase synthesis of substituted benzamidines.