or The Twelve Theses For All Erudite Medicinal Men To Follow, To Purge The Sins Of Abominable Design And To Attain The Heavenly Joys of a Clinical Success
1. Do one change at a time. Keep your molecule small and simple. Cyclize. Fluorine is your friend.
If you make too many intuitive jumps in your structure without knowing the contribution of each change, you will not understand what did what. Your SAR table will become a jungle and you will miss important things. If your compounds become hard to make early in the project, your progress will be slow. It is easy to gain potency by adding a big greasy piece like biphenyl or bromo-substituted benzyl but this back-fires in the longer run. Cyclic compounds have often better properties (cell permeation, PK) , the potency and selectivity can also dramatically improve by restricting the conformations. Replacing hydrogens with fluorines helps to fix the metabolism problem. One can gain additional potency with correctly placed fluorine with only a small penalty on the molecule lipophilicity and size. (Fluorine is also a wonderful NMR label that can be used to follow the chemistry and quickly determine the isomeric purity of compounds).
2. God created sharp SARs.
Don’t despair if the permissible substitution pattern of your active compounds is very narrow – it is a good thing. Lousy and un-druggable molecules are usually from the muddy category (no matter what you change the molecules have always about the same potency).
3. Lipinski rules and Polar surface area scores are only a shorthand.
Lipinski rules and PSA scores are fairly crude but they point in the right direction – Don’t put too many hydrogen bond donors in your molecule if you want a cell permeable orally-active compound. More than 3 Amide/urea NH is bad news. Too many amide and heterocycle NHs together with good hydrogen bond acceptors (carbonyls, hetero-N) in the same flat polyaromatic molecule will likely result in lousy solubility – this is the typical problem with kinase inhibitors. (A small substituent like Cl, Me group next to NH can remedy the solubility/permeability problem). Be careful about sulfonamides and sulfones – these groups are quite polar and can cause problems with cell/brain penetration. Please note that the requirements are more stringent for brain-penetrable compounds.
4. Acidic compounds have high plasma protein binding
If your molecule has acidic groups like carboxyl, tetrazole, isothiazolindione etc, your intrinsic activity has to be very high (single digit nM or better in cells) to ofset the extremely-high plasma protein binding of acidic compound. Greasy molecules are problematic also – but acidic compounds are almost guaranteed to have 99+ % plasma protein binding and hence reduced relative potency in the whole blood assay.
5. Basic molecules have typically improved solubility and cell potency - at a price
More basic amines (primary, secondary) have more pronounced accumulation within cell than less-basic amines (such as N-sunstituted morpholines). Adding amine side-chain to a molecule can also cause lowered selectivity and unexpected organ toxicity. Quartenary ammoniums tend to produce particularly nasty side-effects and should be avoided. Tertiary amines are metabolised by oxidative dealkylation quickly. (Putting fluorine or oxygen beta to amine can suppress the oxidative metabolism and at the same time lower the amine basicity.) Strongly basic molecules have typically very high volume of distribution – which means that due to partition of the compound deep into tissue the dosing has to be increased to achieve decent concentration in the blood – but at the same time the high volume distribution prolongs the half-life of the compound, even if the compound has rather high clearance due to rapid metabolism.
6. Amidines and guanidines are frustrating
It is easy to get an active compound with amidine but it is hard to get it orally active afterwards. Doing chemistry with amidine in the molecule is not fun either. Other not-so-druggable functional groups are hydroxamic acids, aldehydes, thiols, reactive halogens. Nitro groups are a liability but they are not as bad as many people think - though you may want to try to replace a nitro group in the end.
7. Test CYPs
Basic heterocycles and polyaromatic compounds have problem with inhibition or induction of cytochomes. This is undesirable because of the drug-drug interaction liabilities. It is important to test for CYPs inhibition relatively early in the project, especially if the molecule has troublesome pieces like 4-monosubstituted pyridine, 5-azaindole, 1,2,4-triazole, N-monosubstituted imidazole, etc.
8. Do not trust docking, do crystallography early.
Docking can provide some idea in absence of a real information (co-crystal X-ray structure) but most of time the docking amounts to a wishful thinking in front of the monitor. A co-crystal (or at least soaked-crystal) X-ray crystallographic data can be very illuminating. Use the crystallography as a source of ideas but don’t let it rule your design; X-ray data does not address electronic and entropic effects well, and it over-emphasizes hydrogen bonds and steric factors; you may easily get sidetracked by focusing on marginal interactions while overlooking some other important effects. Over-reliance on X-ray in finding additional interactions usually produces ugly compounds that have lots of floppy polar appendages and are hard to make.
9. Get cell-based assay as early as possible to guide your project.
Biochemical data tels you about hidden potential of your compound but cell-based activity is the real thing. You don’t have a real lead compound until you can make it work in cell. Usualy everything that works in cell works also in biochemical assay but this is not true in the opposite direction - things will or won’t work in cell for mysterious reasons and only persistence and patience sometimes helps to find the cell-active version of your molecule. Once you got a decent activity (say, 100nM in biochemical assay) it is important to have cell-based assay as the primary screen; it makes no sense to overoptimise on biochemical assay alone because without cell-based assay you will likely stray in wrong direction.
10. Ignore Caco-2 and do rodent PK tests instead, use human plasma and whole blood
Caco-2 permeability model is useless. Oral absorbtion/brain penetration tests in rodent should be done early in the project. Metabolic studies with liver microsomes can help to identify some metabolically weak spots (use LCMS to identify the metabolites) but microsome studies are not terribly helpful in prioritising the molecules - it is foolish to say “I have to have microsome half-time above 30 minutes.” (If all your molecules have a decent microsomal half-life and suddenly one has a very short one, maybe this one molecule can have a liability towards oxidative metabolism – but this suspicion cannot be taken as a substitute for doing a real PK in rat). Do plasma protein-binding studies with human plasma only – the calf-derived plasma is a poor substitute, often producing misleading results. Do a whole blood assay with human blood. If your advanced compounds are highly crystalline, measure the solubilities and prioritize based on solubility studies
11. Be nice but sceptical
Be nice to your biologists but watch about the reliability of their data - if they got a weird curve or noisy assay they should be forthcoming about it. Don’t give the biologists the entire stock of your compound – you may not get it back.
Don’t force people to work on your ideas – let your lab colleagues choose what part of project they work on, which particular molecules to make. Make the project more enjoyable for them by scaling up the building blocks for the entire lab and by ordering the labor-intensive advanced intermediates from a custom-synthesis company.
12. Patents are not scary
Don’t worry over too much about patents – unless the exact compounds is in the patent experimental examples (with a good preparative procedure and NMR spectra) and is claimed there for the same protein. Very broad patent claims are easy to cast but they are also easy to challenge or skirt; it is almost always possible to get your own narrow patent on things that are within the scope of someone’s patent by describing “new and unexpected” properties of a class of compounds (that were claimed but not documented in the broad patent).
Getting out of patent is much easier than many chemists think - look what Sepracor did, and how many closely-related me-too compounds are there on the market, from the competing companies. Also, the patent-busting changes to the molecule can be quite minimal and can be made very late in the project. It is good to get a broad patent coverage for your project – but if you cannot, all what one needs in the end to have patent-protected is just one compound, the one which eventually becomes a drug.
Note: Totally Medicinal has a related discussion on Tricks of trade in medicinal chemistry.
Update: Derek Lowe has written many times on these subjects In the Pipeline and his take is always insightful. Although there is one idea on which we disagree – Derek claims that “nothing good ever came easy or cheap”. I would like to point out that my mother-in-law did pass away; and I did not have to hire anyone