Lipinski's rules & drug discovery beyond the rule of five

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What are Lipinski’s rules? These are a set of criteria tend to describe the majority of orally available drugs. The criteria are molecular weight (should be equal to or less than 500 g/mol), hydrogen bond acceptors (should be 10 or less), hydrogen bond donors (should be 5 or less), and lipophilicity as described by log P (should be 5 or less). The rule is that any compound that violates two or more of these criteria is at risk of not being orally available, likely because of poor solubility or low membrane permeability. Sometimes this is called the rule of 5 or Ro5. Note that Lipinski’s rules are only about the “A” in ADME, absorption. Lipinski’s rules have nothing to do with hepatic clearance, half-life, safety, or on-target potency. These criteria are only about crossing the GI tract lining. Lipinski’s rules are a bit controversial. There are successful drugs that violate Lipinski’s rules. Let’s see one.
Here is atorvastatin, a drug for the treatment of high cholesterol and one of the most successful drugs ever. Atorvastatin violates two of the Lipinski criteria - molecular weight and lipophilicity. Regardless, atorvastatin is a very successful orally administered drug. Its oral bioavailability is low at 14%, but it was still approved as safe and effective. Compounds like atorvastatin show that guidelines like Lipinski’s rules cannot be used blindly. Each drug is different and must be evaluated individually. Researchers recently have found regular success in developing oral drugs that violate Lipinski’s rules. These drugs lie beyond the Rule of 5. Let’s see two examples.
Here is ventoclax, a drug used to treat certain cancers. The molecular weight is huge - over 800 g/mol, and the lipophilicity is also high at over 6. This drug violates Lipinski’s rules. Regardless, it is an approved orally administered drug. It’s oral bioavailability is, admittedly, quite low.
Here is another - montelukast. This is an asthma drug. It violates Lipinski’s rules in both molecular weight and lipophilicity - especially lipophilicity, over 7. Regardless, it is an orally available drug. In the case of montelukast, the oral bioavailability is actually quite good at 68%. So, these examples show that simple metrics like Lipinski’s rules are guidelines. The exceptions we’ve discussed do not disprove the idea of Lipinski’s rules. Oral drugs do tend to occupy a certain region of molecular space. Oral drugs can exist outside that space, but the risk of having low oral availability is much more likely and must be monitored.

[@Simran-jd4wi]

Thank you buddy 🎉