Often overlooked in early development: how is your compound behaving?

Do the data reflect its molecular type and structure?

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For small molecules, ADME is driven largely by crossing cellular membranes (by passive permeability and/or active transport) and then being metabolised or actively transported (or not). These, often sequential processes, can largely be predicted using modern DMPK SAR – charge (acid/base), lipophilicity (logP) and TPSA (a measure of H-bonding) – all of which are driven by chemical structure. 

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For example, acidic molecules with low TPSA will typically exhibit a short Tmax (well absorbed from stomach due to un-ionized form at low pH) and low volume of distribution (VD, as often highly protein bound).

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In contrast, basic molecules will typically exhibit a longer Tmax (poorly absorbed from stomach due to ionized form dominating at low pH) and high VD (rapid permeation of membranes often coupled with partitioning).

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In addition, for both [charged] molecule types, active transport is likely to be involved in clearance via substrate interactions with membrane bound anionic and cationic transporters.

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In contrast, for lipophilic neutral molecules, metabolism will likely be the primary clearance driver.

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Given this, where are your metabolic soft spots? (metabolically unstable functional groups or regions)

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Are there any structural DILI alerts?

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It is important to review your DMPK data sets early – is your molecule behaving as expected?

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Does your Clearance scale from in vitro - in vivo (IVIVE)?

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If not, prediction and extrapolation to the in vivo situation (IVIVE) may be more difficult leading to a potentially longer and more complex development and an early appreciation of this is important to expedite drug development.