A decentralized solid compound storage facility managed by a centralized electronic platform at a growing drug discovery company.

Within a growing drug discovery company, scientists acquire (either through in house synthesis or purchase) then store, retrieve, and ship solid compound samples daily between multiple locations. The efficient management and tracking of this entire process to support drug discovery is a significant challenge. This article describes a decentralized and cost-effective inventory facility that simplifies the solid compound storage and retrieval process. Standardized storage cabinets from the market are utilized, providing a cost-effective physical infrastructure. The cabinets can be distributed across storage rooms at multiple sites and arranged into spaces with a variety of dimensions, allowing the system to be retrofitted into existing facilities and scaled up easily. We can provide storage close to work areas at each location, minimizing both unnecessary movement of staff and transportation of substances. We have applied a systematic barcoding method to the compound batch identifier that correlates with its compound location. This simplifies the compound registration process as well as the process of finding and returning compounds. Additionally, a centralized electronic platform has been employed to store, update and track solid compound information, such as properties, location and quantity. Compound shipment may be initiated from different sites, and a centralized electronic platform assists the information retrieval process, ensuring each location possesses up-to-date information. The electronic platform we present streamlines the management of compound registration, location tracking, weight updates and shipment information, facilitating seamless record sharing among all stakeholders. Every step of the process can be tracked in real time by the project team. The platform can be flexibly configured to adapt to an evolving set of storage locations, with all information and processes being audited.

An efficient and reliable chemical inventory system at a growing drug discovery company.

Within a growing drug discovery company, hundreds of scientists take and move reagent chemicals on a daily basis. Conveniently updating the locations of tens of thousands of chemical containers in an electronic system is a big challenge. We have an electronic inventory system, but keeping the chemical records up to date relied on scientists finding an available computer in the lab and logging into a system whenever they took or moved a chemical container, taking several minutes. It was all too easy to think that the task could be deferred until later, but the scientist may then forget all about it, leaving the database inaccurate. As a result, searching for the chemicals we need can take a frustratingly long time if they are not where they should be. We have developed an efficient and reliable system, namely ScanStation, to solve this issue. It relies on a low-cost Raspberry Pi attached to a touch screen connected with a barcode scanner. This equipment is always on and placed in strategic locations around all our labs and chemical stores. This new process is much easier. There is no need to remove gloves to log into the computer, and it is just a scan on the barcode and is done. Now when we check the database for a chemical, we get an instant answer that reliably tells us where to find it. All the time we save have a real benefit in our productivity and our scientists can focus on discovering new medicines.

Design and synthesis of a potent, highly selective, orally bioavailable, retinoic acid receptor alpha agonist.

A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARß, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARß (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.

Rapid generation of molecular complexity using "hybrid" multi-component reactions (MCRs): application to the synthesis of alpha-amino nitriles and 1,2-diamines.

Methyleneaziridines can be converted into a wide range of 1,2-diamines and 2-cyanopiperidines in a single operation with the formation of three intermolecular carbon-carbon bonds using a "hybrid" MCR.

Rare example of nucleophilic substitution at vinylic carbon with inversion: mechanism of methyleneaziridine formation by sodium amide induced ring closure revisited.

Intramolecular nucleophilic substitution of the C-Br bond of (E)- and (Z)-2-bromobut-2-enylamines by the pendant nitrogen atom leads to 2-ethyleneaziridines by way of stereochemical inversion at the vinylic carbon atom. The stereochemistry of the products is unambiguously established by X-ray crystallography performed on two derivatives. These cyclizations represent some of the first examples of substitution with inversion in unactivated vinylic substrates. In conjunction with additional deuterium-labeling experiments, the accepted mechanism for this reaction is shown to be flawed.