A solid-phase organic synthesis method has been developed for the preparation of N-substituted-beta-aminopropionic acid oligomers or beta-peptoids 1. Treatment of polymer-bound 4-(benzyloxy)benzyl acrylate 2 with primary amines afforded N-substituted beta-alanines 3. Polymer loadings and product conversions were determined by direct cleavage of resin-bound materials and measurement by (1)H NMR with an internal standard. The NMR method was used to establish loading of all resin-bound intermediates including acrylic acid. Acylation with acryloyl chloride followed by Michael addition of primary amines to the acrylamide allowed preparation of di-beta-peptoids. By a linear set of seven reactions, trimeric N-benzyl-beta-aminopropionic acid was prepared in 67% overall yield. Single-bead FT-IR microspectroscopy was used to acquire spectra of the resin bound mono-beta-peptoids, di-beta-peptoids, and acrylamide intermediates. A combinatorial library of defined mixtures of tri-beta-peptoids was prepared by mixing equimolar amounts of the mono-beta-peptoid resins and carrying them through two sequences of the acylation-Michael addition. The identity of a sample mixture was determined by LC-MS analysis of the cleavage product.

No abstract

No abstract

A solid phase organic synthesis method has been developed for the preparation of substituted methylene malonamic acids and malonic ester mono acids 5. Two substituents are introduced into the core molecule 5 by preparation of unsymmetrical malonic acid derivatives 2, followed by Knoevenagel condensation with aromatic or aliphatic aldehydes, giving resin-bound 4. Evaluation of the scope of these reactions led to the preparation of a 96-member library from a set of eight amines/alcohols (seven amines and one alcohol) and 11 aldehydes leading to 88 substituted methylene malonamic/malonate mono acids 5 and eight unsymmetrical malonamic/malonate mono acids 3. Structural validation and quantitation for every member of the library was obtained by evaluation of 1H NMR and HPLC, respectively. The 1H NMR data were obtained using automated delivery of DMSO solutions of every library member from a 96-deep well microtiter plate to a flow probe-equipped NMR spectrometer. HPLC data were used for determination of the extent of conversion of malonamic/malonate esters 2 to the products 5 by an external standard method. Summary information from the 1H NMR and HPLC data is viewed as plate diagrams for analysis of the final library.

Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures.

No abstract

No abstract

The biochemical and physiological effects of 10 isoxazoles were investigated. The amount of protoporphyrin IX caused to accumulate by the compounds correlated well with their herbicidal activity. Protoporphyrinogen oxidase (Protox) was inhibited competitively in the proximity of the catalytic site. However, the Protox I 50 values of the methyl esters and acid chloride derivatives were lower than expected on the basis of their in vivo herbicidal activity. The results suggest that some tolerance mechanism, other than differential absorption and translocation, may protect the plants against these compounds. The molecular properties of 9 isoxazoles and 2 other well-known inhibitors of different herbicide groups were compared to those of protoporphyrinogen (Protogen). The most active compounds have similar bulk, electronic, and energy properties that approximate half of the Protogen molecule. Furthermore, these compounds have atoms/groups on the ring that generate distinct negative electrostatic potential fields that may mimic the reactive part of the Protogen molecule.