Biomedical subjects

Gergely M Makara

Publications and source records attributed to Gergely M Makara.

10 recordsLinked to original sources

PubMed2006

Hit discovery and hit-to-lead approaches.

Hit discovery technologies range from traditional high-throughput screening to affinity selection of large libraries, fragment-based techniques and computer-aided de novo design, many of which have been extensively reviewed. Development of quality leads using hit confirmation and hit-to-lead approaches present their own challenges, depending on the hit discovery method used to identify the initial hits. In this paper, we summarize common industry practices adopted to tackle hit-to-lead challenges and review how the advantages and drawbacks of different hit discovery techniques could affect the various issues hit-to-lead groups face.

Animals↗

PubMed2005

Improving success rates for lead generation using affinity binding technologies.

Affinity technologies have been applied at several stages of the drug discovery process, ranging from target identification and purification to the identification of preclinical candidates. The detection of ligand-macromolecule interactions in lead discovery is the best studied and most powerful of these techniques. Although affinity methods have been in widespread use for about a decade, only recently have many reports emerged on their utility. Primary affinity screens of large libraries of small molecules or fragments have begun to produce results for challenging targets. Furthermore, in secondary assays affinity methods are opening new avenues to tackle important medicinal chemistry tasks.

Animals↗

PubMed2004

Identification of a small molecule nonpeptide active site beta-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases.

A small molecule nonpeptide inhibitor of beta-secretase has been developed, and its binding has been defined through crystallographic determination of the enzyme-inhibitor complex. The molecule is shown to bind to the catalytic aspartate residues in an unprecedented manner in the field of aspartyl protease inhibition. Additionally, the complex reveals a heretofore unknown S(3) subpocket that is created by the inhibitor. This structure has served an important role in the design of newer beta-secretase inhibitors.

Acetamides↗

PubMed2004

Synthesis, molecular modeling, and evaluation of nonphenolic indole analogs of mycophenolic acid.

Based on the promising activity of an indole-3-carboxamide derivative, a nonphenolic analog of mycophenolic acid (MPA), we report herein the synthesis of a compound containing two important features for the activity of MPA, the ring methoxy and methyl. The synthesis was accomplished using two strategies; a method dependent on stepwise building of the hexenoate side chain followed by the indolecarboxamide ring system, and a convergent route that depended on 1,3-sigmatropic rearrangement as a key step. Docking experiments on both Chinese Hamster and Human Type-II inosine monophosphate dehydrogenase (IMPDH) showed that this compound has potential binding interactions with the NAD site. The analogs showed no activity against MCF7-S, MCF7-R, or IGR-OV1 cancer cells.

Animals↗

PubMed2003

A reagent-based strategy for the design of large combinatorial libraries: a preliminary experimental validation.

Combinatorial library design can be carried out at either the reagent or the product level. Various reports in the literature have come to conflicting conclusions in favor of one over the other. In this paper a reagent-based screening library design strategy is presented. The method relies on analysis of scaffolds and building blocks separately to define the overall diversity in a compound file. The primary diversity selection by properties relevant for molecular recognition and by redundancy is followed by the application of filters for molecular properties known to be relevant for drug-likeness. Filter properties are rapidly estimated at the product level using a fragmental estimation approach. Initial experimental data suggest that high diversity in vast screening libraries can be achieved by carefully applied reagent level analysis. A potential role of diverse screening libraries in chemical genomics (pharmacological knockouts) is also discussed.

Chemistry, Pharmaceutical↗

PubMed2002

Solid-phase synthesis of 3-alkylamino-1,2,4-triazoles.

[reaction: see text] A solid-phase synthesis of trisubstituted 3-alkylamino-1,2,4-triazoles has been developed. The synthesis utilizes immobilized N-acyl-1H-benzotriazole-1-carboximidamides as key intermediates. Cyclization with hydrazines under mild conditions furnishes the title compounds with regioselectivity and high purity.

Chromatography, High Pressure Liquid↗

PubMed2002

New developments in chemical library synthesis. Norbornenyl tags for use in phase-switching, sequestration, capture-release and soluble support applications.

A new, general chemical library purification platform is reviewed. This platform makes broad use of (oxa)norbornenyl-tagged reactants, reagents, catalysts, sequestration-enabling reagents and scavengers, in combination with Grubbs catalyst-mediated ring-opening metathesis polymerization (ROMP) reactions as an in situ polymerization purification technique. Extensions of this platform involve the use of preformed ROMP supports in synthesis, and polystyrene-supported Grubbs catalysts, which perform in a boomerang fashion.

Animals↗

PubMed2002

Recent advances in chemical library synthesis methodology.

The first part of this review highlights recent advances in polymer-supported reagents, catalysts, reactants and sequestrants. Particular attention is given to recent advances in polymer-supported oxidants, transition metal catalysts and polymer-supported reactants, including acyl groups, guanidinyl groups, alkyl groups and various classes of nucleophiles. This second part of the review highlights recent advances made in the areas of chemical tagging and phase-trafficking techniques, all of which have enabled further advances in the methodology of solution-phase chemical library synthesis.

Animals↗

PubMedDate not supplied

Combinatorial synthesis of substituted biaryls and heterocyclic arylamines.

In this paper, we report very general conditions that enable palladium-mediated coupling reactions on the solid support. A wide variety of biaryls and arylamines (including pyrimidines) have been synthesized using this protocol. The chemistry facilitates a combinatorial approach to the production of large numbers of medicinally relevant heterocyclic structures.

Journal Article↗

PubMedDate not supplied

Versatile solid-phase synthesis of trisubstituted 1H-pyrido[2,3-d]pyrimidin-4-ones and related heterocycles.

A solid-phase synthesis of trisubstituted 1H-pyrido[2,3-d]pyrimidin-4-ones has been developed. The synthesis utilizes solid-phase bound N-2,6-dichloronicotinoyl-1H-benzotriazole-1-carboximidamides as key intermediates. Sequential substitution of benzotriazole and the two chlorines furnishes the title compounds with regioselectivity and high purity. Application of the method to various disubstituted analogues is also demonstrated.

Combinatorial Chemistry Techniques↗