Skip to main content

Chemical News

Rule of Ten?

I see from See Arr Oh’s Twitter feed (from the ACS meeting in San Francisco) that he’s attending a talk on macrocycles (and how some of them have bizarrely good PK and other properties. The speaker suggested a “Rule of 10” for orally available macrocycles: ring size greater than 10, molecular weight under 1000, and clogP around 10. That’s quite a set.
The problem is, I’ll bet that the percentage of reasonable-looking compounds that fit those criteria but are actually orally active is quite small. Probably significantly smaller than the percentage of reasonable-looking compounds that fit the Lipinski Ro5 criteria and behave decently. Orally-available macrocycles seem to have some sort of internal-hydrogen-bond thing going on that we don’t really grasp, and you’d have to figure (hydrogen bonds being what they are) that there are far more ways to get it wrong than to get it right.

21 comments on “Rule of Ten?”

  1. Barry says:

    Lipinski did warn that internally-satisfied H-bonds don’t count in the R-o-5 tally.
    For a macrocycle, you might even discount internal H-bonds satisfied by a bridging/bound water?

  2. annon 2 says:

    Another rule that some will think is gospel, and others will correctly use only to discard.

  3. Mike W says:

    I suggest the Rule of no Rules. It goes like this:

  4. Boghog says:

    Good observation. Also internal H-bond in macrocycles effectively reduce the number rotatable bonds. According to Veber (J Med Chem. 2002;45(12): 2615-23; DOI: 10.1021/jm020017n), rotatable bonds have a larger influence on bioavailability than molecular weight. Hence a macrocycle made rigid by buried H-bonds stands a good chance of being orally bioavailable.

  5. Anony-brain says:

    I totally agree. I call it the rule of zero.

  6. Boghog says:

    @3, @5: Carefully derived rules based on sound data is thinking.

  7. Chrispy says:

    Anyone know whatever became of Ensemble’s anti-IL17 macrocycle? I just looked at their website and they optimistically state: “The company expects this rapidly advancing IL-17 program to produce an orally active development candidate in early 2013.” It looks like they were able to achieve some oral bioavailability in mice with a boatload of Kolliphor as an excipient.
    Actually, there is very little news on Ensemble for over a year now — are they OK? I liked their approach (once they got away from the DNA-directed synthesis thing). Anyone out there know what’s up with these guys? I thought they were the leaders in macrocycle space…

  8. Anony-brain says:

    @ Boghog
    Maybe you are right. However, when I ask medicinal chemists with 20+ years of experience and a good number of drugs in the clinic/market, they tell me consistently that compounds that become drugs generally don’t follow the patterns of close analogs (the rule), but rather they are an exception…
    As they say, “threading the needle”… But hey, it’s a free country!

  9. Anonymous says:

    Rule of 10 brain cells?

  10. mr NMR says:

    We still dont understand peptide structure!

  11. mr NMR says:

    We still dont understand peptide structure!

  12. Anonymous says:

    I agree with the comments that the “rules” are annoying and misleading, however, the speaker didn’t advocate a “rule of 10”, he suggested that for compounds that exist beyond the rule of 5 and against difficult targets the upper limit (emphasis upper limit) of designable oral drug space is MW less than 1000 Da, ClogP less than 10 and PSA less than 250. Also the paper has been accepted, so it should come out soon, then we can judge it for ourselves.

  13. Anonymous says:

    Actually, once I talked to Chris Lipinski about his “Rule of 5”, and he said it should never be thought of as a rule, only a guide to improve success rates…
    Unfortunately many left-brained people only know how to deal with rules and not guidelines.

  14. Brad says:

    Hello Derek and In The Pipeline community, I am one of the authors of the talk and data in question (accepted and coming out soon in Chemistry and Biology); and agree that none of these things are rules to apply in all situations, you must decide to apply it or not. These guidelines fail when they are misused or not understood, we should apply some advice from @3 Mike W, “think”, particularly on “is this guideline/rule relevant for my situation?”. For example, Lipinski’s guidelines/rule of 5 have their place in drug discovery if you have a “highly druggable” site but are less useful if you are looking to develop drugs against some of the more recent, larger, flatter and more difficult binding sites. Hence, the “rule of 10” may be helpful in design of compounds against these difficult targets where working within rule of 5 space is difficult. Ultimately the application of the guidelines are up to the user (cf. @14), in the paper we emphasize that oral bioavailability does not simply end at the rule of 5 but you should have the knowledge of what difficulties and advantages lie beyond it and that compounds within the “rule of 10” have at least some chance of being orally bioavailable. As Derek rightly points out, there are many parenteral drugs in this space also. We also discuss topics such as intramolecular hydrogen bonding, transporters etc. that influence properties “beyond the rule of 5” to maximize your chances.

  15. Boghog says:

    Thanks for your post. I am anxiously awaiting reading your paper. However I cannot help but thinking that much of this is not new. Orally available macrocyclic antibacterial agents with molecular weights in the range of 700-900 and cyclosporin, molecular weight of 1200 have been known for a long time. Veber’s data (J Med Chem. 2002;45(12): 2615-23; DOI: 10.1021/jm020017n) suggests that the RO5 emphasis on molecular weight may be misplaced. Also Lipinski himself stated if transporters are involved, the RO5 does not apply.
    @14: Agree completely. Paul Leeson (Nature Reviews Drug Discovery 2007; 6 (11): 881–90. doi:10.1038/nrd2445) and others have shown that while it is certainly possible to develop drugs outside of the R05 space, RO5 candidate drug outliers have a higher attrition rate in clinic. Furthermore as stated above there are the obvious outliers like macrocycles.

  16. Brad says:

    You are correct, we certainly do not claim to be the originators of beyond rule of 5. The paper is the first detailed review of oral compound beyond the rule of 5. We compiled a near comprehensive list of approx. 500 drugs greater than 500 Da and then split the data into what we term “extended Ro5 space” which is still close to Ro5 space and the 85 oral compound remaining in “beyond rule of 5” (bRo5) space, the relevant literature on these bRo5 drugs was then examined in detail. For example, if i was to ask you, which compounds bRo5 use intramolecular hydrogen bonding (IMHB)? many say, cyclosporin A and leave the list there, however there are other IMHB macrocycles, such as the rifamycins and ivermectin as well as the non-macrocyclic HCV NS5A inhibitors and HIV-1 protease inhibitors. This is not new news either, they have all been reported previously but none have brought it all together for all bRo5 drugs and candidates, some great papers though include Med. Chem. Commun., 2011,2, 669-674, DOI: 10.1039/C1MD00093D and Bioorg. Med. Chem. Lett. 2012 Nov 1;22(21):6540-8 DOI: 10.1016/j.bmcl.2012.08.059. Similarly, name the compounds bRo5 for active uptake? We found only 3 of the 85 compounds have evidence of active uptake in the intestine, two are lipid prodrug mimetics in clinical trials specifically designed and the other one is debated in the literature. An unexpected fact for myself, I thought more compounds bRo5 would have been linked to active uptake in the intestine, however we found no such evidence for the vast majority of bRo5 compounds. Though, this may be because we haven’t discovered it yet. We also look at efflux transporters and saturation, dosage, distribution effects, formulation as well as the origin of compounds. The risks bRo5 are discussed including toxicity, solubility, poor permeability, low bioavailability etc. The review is large and covers a lot of things associated with bRo5. The novelty in the paper is its comprehensive and detailed analysis of bRo5 compounds, I have not seen any paper provide a full list of bRo5 compounds nor attempt to compile data and analyse the multiple suggested reasons why these compounds are orally bioavailable. Many focus on only physicochemical analysis or a single property such as intramolecular hydrogen bonding and then speculate on such topics as active uptake in attempt to exclude many other compounds bRo5.

  17. Anonymous says:

    I wish this paper had come out 15 years ago. The CEO of the biotech company I founded killed our lead compound (and eventually the company itself), just because it didn’t “obey Lipinski’s Rule of 5”, despite the fact we had *proven* it to be orally bioavailable and even get into the brain.
    I hate rules. They are made to be broken.

  18. Boghog says:

    Thanks for the clarification. You are right. I don’t think anyone has brought it all together like you describe. I look forward to reading your paper when it is published.

  19. London Chemist says:

    “I hate rules. They are made to be broken.”
    I find a better quote is:
    ” Rules are for the guidance of wise men and the adherence of fools”

  20. Björn says:

    for the ones waiting for our publication “Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates”, here is the URL:
    Looking forward to your comments,

Comments are closed.