Kevin W. Moore

4-N-linked-heterocyclic piperidine derivatives with high affinity and selectivity for human dopamine D4 receptors

The syntheses of a number of different N-linked heterocyclic pyrazole replacements based on the structure 1 are described (compounds 3-12) as hD4 ligands. After further optimisation the best compound identified was 13 which has high affinity for hD4 (5.2 nM) and >300-fold selectivity for hD4 receptors over hD2 and hD3 receptors.

Routes to 4-substituted analogues of the glycine/NMDA antagonist HA-996. Enantioselective synthesis of (3R,4R) 3-amino-1-hydroxy-4-methyl-2-pyrrolidinone (L-687, 414).

Abstract Glycine anion (4) and glycine cation (8) synthons are used in efficient syntheses of 4-substituted analogues of HA-966 (1). A stereospecific route to cis derivatives involves hydrogenation of enamines such as 16. Introduction of a chiral auxiliary leads to an enantioselective synthesis of 2a (L-687, 414).

Derivatives of 1-hydroxy-3-aminopyrrolidin-2-one (HA-966). Partial agonists at the glycine site of the NMDA receptor

The in vitro activies of 4-substituted and bicyclic analogues of the glycine-site NMDA partial agonist HA-966 (1) reveal strict structure-activity requirements reflecting subtle conformational and steric requirements for receptor binding. The most active compounds have cis-4-methyl or hydroxyl substituents and it is suggested that the in vivo anticonvulsant activity and good brain penetration of the optimal compound (+) 2 (L-687,414) result from the high fraction of (+) 2 which is not ionised at physiological pH.

Implementation of a High Specification Dual-Arm Robotic Platform to Meet Flexible Screening Needs

The need for a high degree of flexibility within compound screening is a requirement throughout the drug discovery industry. The demands made of automation technology are becoming increasingly sophisticated as assay formats diversify and confidence in screening automation grows. To meet these demands for high-performance and flexibility, MSD with RTS Life Science have developed and installed a dual-robot arm screening system at our Terlings Park site to support early stage drug discovery. Plate transport on the system is via two articulated robotic Staubli arms. The system has two operating modes, combined, with the entire system operating in unison; and independent with each robot arm acting independently to perform two different screens in parallel. Additional flexibility is provided by the SPRINT software ‘dynamic batch scheduling’ feature. This allows for the scheduling of multiple screens to run automatically and for extra plates to be added and new screens to be added once the system is running without the need to stop the system and reschedule the work plan. The utility of the systems is exemplified in a kinase counter screening mode in which four different kinase assays are run against the same set of compounds in one robotic run.

Anticonvulsant activity of glycine-site NMDA antagonists. 1. 2-carboxyl prodrugs of 5,7-dichlorokynurenic acid

Anticonvulsant activity in the DBA/2 mouse audiogenic seizure model has been obtained in water-soluble prodrug esters of the glycine-site NMDA antagonist 5,7-dichlorokynurenic acid (1), leading to the 1-methyl(2-dimethylamino)ethyl ester 10 (ED50 62 mg/kg i.p.), which shows no behavioural stimulation at the anticonvulsant dose.

Effects of five-membered ring conformation on bioreceptor recognition: identification of 3R-amino-1-hydroxy-4R-methylpyrrolidin-2-one (L-687,414) as a potent glycine/N-methyl-D-aspartate receptor antagonist

Syntheses of the 4-methyl (2 and 3) and [3.2.1]bicyclo (4 and 5) analogues of the glycine/N-methyl-D-aspartate (NMDA) antagonist 3-amino-1-hydroxypyrrolidin-2-one (HA-966, 1) provide evidence that glycine receptor recogntion requires the energetically less favoured 3-pseudoaxial conformation of the pyrrolidone ring, resulting in a 5–10 fold improvement in activity with the 3R-amino, 4R-methyl derivative (2a, L-687,414).

Efficient Sample Logistics: From the Chemist to the Assay Plate and beyond

A seamless workflow from the medicinal chemist to the screening collections and then to project team assays for new chemical entities has been achieved, by using 1.4-ml 2D bar-coded tubes, an automated tube store system, and a database built in-house. A process of sample collecting, logging, shipping, and sample reformatting has been established with a ComPOUND/ ComMOTION automated tube store system at the heart of the process.

Synthesis of penems by ring contraction of a 2-thiacephem

2-Thiacephems prepared from penicillanic acid undergo ring contraction to penems with triphenylphosphine.