Seventy-five percent of drug candidates do not reach the clinical trial phase mainly due to poor pharmacokinetics in animal studies (1). Since so many compounds fail in late stage testing, the current trend is to study the pharmacokinetics of lead compounds as early as possible. One of the most important elements of pharmacokinetics is lipophilicity, or a compound's affinity for fat. Usually, the more water soluble a compound is, the lower its lipophilicity. Low water solubility (high-lipophilicity) compounds have a limited oral bioavail-ability but are usually easily metabolized. On the other hand, low-lipophilicity compounds have poor membrane permeability since membranes are partly composed of fat.
During the lead modification process, Lipinski suggests "the rule of five'' guide to improve oral bioavailability. Any compound (with the exception of antibiotics, antifungal agents, vitamins, and cardiac glycosides) with two or more of these characteristics is likely to have poor oral absorption and or distribution:
• molecular weight higher than 500
• more than five H-bond donors
• more than 10 H-bond acceptors
It is called "Lipinski Rule of Five'' since the cutoffs values for each four parameters are all close to five or are a multiple of five.
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