Situation: The client had compounds with novel structures for use in the treatment of respiratory disorders. The first batch of analogs had been synthesized and was in the process of going through in vivo testing. Potential ADMET problems to be addressed by the medicinal chemistry program needed to be identified.
Nothing was known about the ADMET properties of the compounds. No in vitro assay for efficacy was available. Preliminary in vivo results did not match with predictions of efficacy based on structure.
The cost and duration of in vivo testing required careful pre-selection of compounds. It was necessary to identify the ADMET issues associated with each compound and to come up with a paradigm to apply to the compounds to take forward to the animal efficacy and pharmacokinetics studies.
Client scientists consulted with Apredica on the chemistry of the compounds. Apredica scientists gave suggestions regarding structural flaws that may be causing inconsistencies in in vivo results. To test this hypothesis, Apredica conducted a battery of assays to determine drug-drug interactions, stability, solubility, Caco-2 permeability and cytotoxicity of the compounds.
Results: Apredica identified the major ADMET liability: fast plasma metabolism of the compounds. Following discussions of the data, Apredica and client scientists designed and implemented custom experiments to confirm the mechanism of liability.
Apredica then designed custom assays to screen compounds prior to in vivo testing and ranked the compounds according to their ADMET liability.
The client implemented the strategy, which resulted in a rational funnel from early in vitro tests to in vivo efficacy. The fewer compounds selected for in vivo efficacy had significantly better properties that did not obscure efficacy results. Chemists had clear structure activity relationship (SAR). A pre-clinical candidate and a backup series were selected a few months after selecting the strategy. With the data provided by Apredica, the client was able to prioritize compounds for animal studies.
Filed Under: Drug Discovery