Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors

Abstract

Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.

A platform for automated nanomole-scale reaction screening and micromole-scale synthesis in flow

“…It has therefore become routine to run screens of hundreds of reactions that, in combination with high-throughput analytics such as ultraperformance liquid chromatography-mass spectrometry (UPLC-MS), achieve a rapid turnaround from design all the way through to results in 2 to 3 days, drastically altering the cost/benefit analysis of prospective reaction screening. This approach expands the potential structural diversity of investigated compounds and saves time and resource investment downstream in the development phase if efficient chemistries discovered through HTE are already in place (5).…”

Stereoselective construction of sterically hindered oxaspirocycles via chiral bidentate directing group-mediated C(sp3)–O bond formation

“…In order to demonstrate the synthetic utility of the current method, for the first asymmetric synthesis of the potent diacylglycerol acyltransferase (DGAT1) inhibitor ( 7 ), we treated 2o as outlined in Scheme 2 . 20 Removal of the DG from 2o gave the carboxylic acid 4 , which was readily converted to the intermediate 5 by esterification followed by N -Boc deprotection with TFA. S N Ar displacement of the pyridyl fluoride of 6 was subsequently executed with oxa-azaspirocyclic amine 5 by heating to 110 °C using NaHCO 3 as the base in the solvent N -methyl-2-pyrrolidone (NMP).…”

Streamlining bioactive molecular discovery through integration and automation

“…11,23 Such reactants tend to perform systematically poorly in chemical reactions, resulting in a significant drift in logP between designed and produced arrays. 23 Several teams [24][25][26][27][28] have therefore developed highthroughput approaches for the optimisation of reactions within medicinal chemistry workflows.…”