Skip hydrogen altogether: Deuterated derivatives you could (should) make in the first instance

Carbon-Deuterium bonds are shorter than Carbon-Hydrogen bonds. As a consequence, they can be more stable to oxidative processes (This is called DKIE: Deuterium Kinetic Isotopic Effect). So, if the rate limiting step in a metabolism pathway is oxidation of the C-H bond, the C-D analog should display lower metabolism rate. Talk about the most neutron-efficient way to improve your LipMetE!

There are many reviews on the medicinal chemistry use of deuterium but the 2019 review by Tracey Pirali and colleagues (JMedChem2019) just stands out for me (and so does their follow-up 2023 one (NatureRevDrugDisc2023)). The authors did an incredible job of collecting in vitro and in vivo data for almost all of their examples. Even more importantly, they compiled data on what to expect when introducing a deuterium in different positions in your molecule.

In the case of CYP450 mediated metabolism, the table below sums up when deuterium should be expected to work as a metabolism reduction strategy (and when it is less likely).

(Of note, in their 2023 review, the authors rate the impact on alkyl deoxidation higher than in the table above).

A nice illustration comes from the fact that the majority of the deuterated compounds that made it to the market or in the clinic actually have deuterated ethers or deuterated amides, the ones in the high DKIE column.

Starting with the impressive TYK2 inhibitor deucravacitinib 1 (JMedChem2019a, JMedChem2019b) where the impact of deuterium slowed down the demethylation of the amide (the primary amide metabolite was plagued with poor kinase selectivity and associated tox limitations). 2 and 3 are deuterated versions of approved drugs ( the RAF and other kinase inhibitor sorafenib and the androgen receptor antagonist enzalutamide respectively) with improved PK in clinic. 4, a dual FGFR2/3 inhibitor, was designed (among other compounds) by scientists at Incyte to lower the metabolism of the methyl amide lead, which it successfully achieved (JMedChem2022). Deutetrabenazine 5 was the first approved deuterated drug specifically designed to extend half life. TGFβR1 inhibitor 6 (ACSMedChemLett2018) was designed by a team at BMS. Unfortunately, the in vitro values for the hydrogen to deuterium pair were not given but the team highlighted that the main impact of the deuterium in this case was on CYP inhibition (this was also surprisingly mentioned for compound 4).

This list is not exhaustive but certainly highlights that the strategy has been quite successfull (all the way to market)...so...

Probabilistically, a deuterated methyl amide and a deuterated aromatic methoxy should be better overall compounds, matching potency and physprops of their hydrogen analogs and having most likely improved metabolic fate...so why make the hydrogen analog at all?

There will be some exceptions to this, especially if you are unfortunate enough to run into some metabolism switching. This occurs when metabolism of the deuterated analog switches to another part of the molecule and can lead to significantly increased turnover rates (one of the most famous examples is around maraviroc as mentioned in the Pirali review (JMedChem2019); another recent example can be found here ACSMedChemLett2022). However, I would argue that this is a blessing in disguise as it will highlight another likely metabolic liability in your series which was probably bound to appear sooner or later (when exploring higher logD for instance).

The Pirali reviews also highlight another case where Deuterium should also be prioritised as a strategy: in the case of aldehyde oxidase, oxidation of the C-H bond also represents the rate limiting step. So it's not surprising to start seeing clinical candidates incorporating deuterium on heterocycles ortho to sp2 nitrogens.

8 is Vertex' DNAPK inhibitor clinical candidate VX-984 while 7 represents an elegant solution by Shangai Institute of Materia Medica scientists to a solubility related toxicity issue of an AO mediated metabolite of JNJ-38877605 (ChemResTox2018 ; Solubility mediated toxicity post).

In a similar way, should we even synthesise 2-hydrogen quinolines or 4-hydrogen pyrimidine compounds or directly go for the deutero-version?

If the latest Pfizer synthesis paper (ACSMedChemLett2023) gives us any insight on their view on deuterium as an aldehyde oxidase mitigation strategy, the fact that they are developing methodology to introduce deuterium on pyrimidines makes me think, it certainly comes up a lot in their design meetings !

Might as well directly go for the better compound...at least for methyl amides, methoxyaromatics and quinolines....

15/02/2024 edit: The aldehyde oxidase review (JMedChem2019) published by UCB scientists gives a few other examples of deuterium solving AO metabolism.