The SAR of the lead compound 3, a novel ligand for the alpha(2)delta subunit of voltage-gated calcium channels, was rapidly explored. Utilizing a parallel solution-phase Sn2Ar coupling approach, a focused library was obtained. The library was evaluated in vitro and afforded a series of analogues with improved potencies. The SAR trends of the library are also described.

A novel class of 6-aryl-6H-pyrrolo[3,4-d]pyridazine ligands for the alpha2delta subunit of voltage-gated calcium channels has been described. Substitutions in the aryl ring of the molecule were generally not tolerated, and resulted in diminished binding to the alpha2delta subunit. Modifications to the pyridazine ring revealed numerous permissive substitutions, and detailed SAR studies were carried out in this portion of the molecule. Replacement of the pyridazine ring methyl group with an aminomethyl functionality provided greatly improved potency over the initial lead. The initial lead compound displayed good rat pharmacokinetic properties, and was shown to be efficacious in the Chung model for neuropathic pain in rats.

The SAR of the lead compounds 2a and 2b was rapidly explored. Utilizing a parallel solution-phase Suzuki coupling approach, in tandem with strong cation exchange resin (SCX) purification afforded the desired focused library. The library was evaluated in vitro, a ninefold potency increase was achieved and the preference for ortho substitution of moderate steric bulk of the fourth, phenyl ring was identified. In addition, dimethylisoxazole, as a heterocyclic replacement for the phenylic ring of the lead compound, was also identified by this approach.

A series of 1,2-disubstituted pyridylalkenes have been prepared using a solid-phase resin approach. This approach takes advantage of a novel alkynyldihydropyridine to alkenylpyridine isomerization.

REsin Activation/Capture APproach or REACAP Technology, a novel approach to the synthesis of compound libraries, capitalizes on the formation and retention of a resin-bound reactive intermediate, which can be subsequently transformed into a stable, covalently attached molecule. Any unreacted “reactive intermediate” is quenched and removed from the resin upon work-up, leaving only the desired product on the solid support. In contrast to more traditional solid-supported chemistry that must address issues such as resin-loading, capping of unreactive functionalized moieties, and reaction yields, REACAP offers an attractive alternative with the focus more on the purity of the released products and less on yield. In an endeavor to generate truly non-peptide leads, we describe herein the synthesis of N-acyl-2-substituted-dihydro-4-pyridones, dihydro-4-pyridones, 4-ketopiperidines, tetrahydropyridines, and 2-acyl-3,7,8-substituted-5-oxo-2-azabicyclo[2.2.2]octane and triaza analogs using REACAP Technology. © 2000 John Wiley & Sons, Inc. Biotechnol Bioeng (Comb Chem) 71:78–84, 2000.

The resin-bound enol ether scaffold generated using the Resin Activation/Capture Approach (REACAP) Technology was further elaborated via a stereospecific Diels-Alder addition to afford a series of highly rigid substituted 5-oxo-2-azabicyclo[2.2.2]octane and triaza analogs. (C) 1999 Elsevier Science Ltd. All rights reserved.

Resin Activation/Capture Approach (REACAP Technology) has been used to synthesize dihydropyridone scaffolds on solid support. (C) 1997 Elsevier Science Ltd. All rights reserved.

Resin Activation/Capture (REACAP) Technology was used to prepare N-acyl-2-substituted-dihydro-4-pyridone analogs.

The resin-bound dihydropyridone scaffold generated using the Resin Activation/Capture Approach (REACAP) Technology was further elaborated to afford 2,4-disubstituted pyridine and tetrahydropyridine derivatives. This process car be envisaged as the functionalization of pyridine analogues on solid support by a traceless linker approach.

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A solid-phase split-mix organic synthesis method was developed which, by two synthetic steps, converts polymer-bound aldehyde I into resins III. Step one consists of dividing I into three equal portions in separate flasks, condensing each with a different ylide, and subsequently recombining to give II. This mixture of beads was again equally divided into three flasks, and each flask treated with a thiolate Michael donor. Prior to recombining the contents of each flask (i.e., sub-library), samples of each resin were removed and incubated with a THF/HCO2H mixture to liberate the small molecule products. GC-MS established that each sub-library (A, B, and C) contained the three anticipated formate esters. In addition, GC analysis illustrates that, while there were no purification steps involved in this solid-phase analogous organic synthesis save bead washings between steps, the desired products are obtained in excellent purity. Single bead (200–400 mesh) selection from library D (combined sub-libraries A-C), solvolysis, and GC-MS analysis shows that compound identities can be established on a per bead basis.

Mass spectrometry is used to develop an analytical method for a new class of organic oligomeric material, beta-ketolactones. Three different series with varying oligomeric sizes are examined. The oligomers may form at least two different structures, a macrocyclic and a catenane ring. Fast atom bombardment coupled with Fourier transform mass spectrometry provides a rapid and convenient method that provides both molecular weight information and abundant fragment ions that are structurally relevant. All the compounds are found to work well with the mass spectrometric analysis. Electrospray ionization coupled with triple-quadrupole mass spectrometry was also evaluated and found to yield results that are similar to FAB. On the basis of the FAB and the low-energy collisionally activated dissociation spectra, we conclude that these compounds are macrocyclic rings and not catenanes.

An acylketene mediated cyclization protocol delivers a series of cyclic oligolides, the largest characterized cyclic oligolide having a 77-membered ring. 6-(ω-Hydroxyalkyl)dioxinone analogs were prepared and cyclizations were conducted under a variety of conditions in refluxing toluene. 1H-NMR, 13C-NMR, and several different mass spectrometric techniques were employed to verify the cyclic nature of these oligolides.

The concept of controlled fragmentation for the analyses of mixtures is developed in the fast atom bombardment/Fourier transform mass spectrometry of a new oligomeric class of cyclic beta-keto lactones. These cyclic oligomers produce fragments during ionization with masses that are identical to smaller homologues. By using the proper alkali metal ion, dissociation reactions are limited to loss of the metal ions. In this way, fragments do not interfere with the identification of quasimolecular ions. From competition experiments involving several alkali metals, Cs+ was identified as the best candidate to analyze mixtures. It enhances the quasimolecular ion signal but does not produce Cs+ coordinated fragments. The metal was then used to analyze a reaction mixture to elucidate the oligomerization mechanism.