Rules for Rapid Property Profiling from Structure Chapter 4. Rules for Rapid Property Profiling from Structure 2013.09.27 양혜란

Chapter4. Rules for Rapid Property Profiling from Structure Overview Lipinski and Veber rules are guidelines for structural properties of drug-like compounds. Rules are effective and efficient means of rapidly assessing structural properties.

The rules were used at Pfizer for a few years prior to 4.1 Lipinski Rules The rules were used at Pfizer for a few years prior to their publication and since then have become widely used. Poor absorption or permeation are more likely when : > 5 Hydrogen bond donors (expressed as the sum of all OHs and NHs) > 10 Hydrogen bond acceptors MW > 500 logP > 5 (or MlogP > 4.15) Substrates for biological transporters are exceptions to the rule

4.1 Lipinski Rules R-OH R-COOH R-NH2 R-NH-R’ R-CO-R’ R-COO-R’ R-O-R’ R-C≡N Thus, an increasing number of hydrogen bonds reduces partitioning from the aqueous phase into the lipid bilayer membrane for permeation by passive diffusion.

The rules were used at Pfizer for a few years prior to 4.1 Lipinski Rules The rules were used at Pfizer for a few years prior to their publication and since then have become widely used. Poor absorption or permeation are more likely when : Molecular weight(MW) is related to the size of the molecule. As molecular size increases, a larger cavity must be formed in water in order to solubilize the compound, and solubility decreases.  absorption ↓ Membrane transporters can either enhance or reduce compound absorption by either active uptake transport or efflux, respectively. Thus, transporters can have a strong impact on increasing or decreasing absorption. > 5 Hydrogen bond donors (expressed as the sum of all OHs and NHs) > 10 Hydrogen bond acceptors MW > 500 logP > 5 (or MlogP > 4.15) Substrates for biological transporters are exceptions to the rule Increasing logP also decreases aqueous solubility, which reduces absorption.

Molecular flexibility, polar surface area (PSA), and hydrogen 4.2 Veber Rules Molecular flexibility, polar surface area (PSA), and hydrogen bond count are important determinants of oral bioavailiability. ≤ 10 rotatable bonds ≤ 140Å2 PSA, or ≤ 12 total hydrogen bonds (acceptors+donors)

Pardridge proposed rules for blood-brain barrier permeability. 4.3 Other Rules Pardridge proposed rules for blood-brain barrier permeability. MW ≤ 400-600 Da The total hydrogen bond number ≤ 8 Oprea proposed the “rule of 3” for lead-like compounds. H-bonds, molecular weight, and logP, which deteriorates drug-like properties. (see Chapter 20)

4.4 Application of Rules for Compound Assessment Figure 4.1 Doxorubicin H-bond donor < 5 H-bond acceptor < 10 MW < 500 logP ≤ 5 ≤ 10 Rotatable bonds ≤ 140Å2 PSA ≤ 12 total hydrogen bonds Lipinski Rules Veber Rules H-bond donors = 7 Rotatable bonds = 11 H-bond acceptors = 12 PSA = 206 MW = 543 Total H-bonds = 19 ClogP = -1.7

4.4 Application of Rules for Compound Assessment 2000-fold increase in potency H-bond donor < 5 H-bond acceptor < 10 MW < 500 logP ≤ 5 ≤ 10 Rotatable bonds ≤ 140Å2 PSA ≤ 12 total hydrogen bonds

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