Drug-like characteristics

TABLE 16.2. Evolution of acceptable predictors of drug-like characteristics or desirable biopharmaceutic and pharmacokinetic properties... 

Once a discovery compound has been identified with overall drug-like characteristics (good potency, selectivity, safety, and PK), that compound will be selected for advancement into clinical development. The next important PK activity is the quantitative projection of the human PK (20, pp. 207-228). Such information is useful for the planning of the preclinical and clinical development programs. Equation 6 can be used to estimate the clinical half-life if we can estimate CL and V. Two approaches can be used to estimate CL. 

Ideal metrics of an optimized lead to provide drug-like characteristics... 

New intelligent formulations developed in an effort to rescue certain candidates that may lack certain inherent drug-like characteristics. These intelligent formulations can improve the half-life of the drug, can enhance its absorbance, and can blunt C , when needed. These formulations offer new opportunities to get candidates to patients faster and can also enhance the intellectual property position of a certain drug. On the other hand, these formulations can be challenging to the process chemist as they sometimes may require specific final forms with specific particle size distributions that may not be attainable by common means. 

Fig. 7. A popular indicator of oral bioavailability, excluding effects due to active transport and first-pass metabolism, is the number of rule of 5 violations (6). In this case, the profile of the number of violations for an optimized library (solid bars) is shifted to lower values, relative to the full virtual array (unfilled bars), indicating that optimization selected a library with improved drug-like characteristics. This shift could be made more pronounced by more heavily weighting the Desirability term in eq. 1 at the expense of some diversity.

Molecular structure has been shown to influence absorption. By examining the structural characteristics of drugs that were in use, certain common characteristics of well-absorbed molecules were identified, commonly referred to as the rule of five. Some investigators have used this as a basis for characterizing the drug-likeness of a lead chemical. Other factors also come into play including receptor activity, metabolism profile and for CNS-active compounds, an ability to cross the blood-brain barrier. 

The stimulation of locomotor activity by MDMA and the importance of mesolimbic dopamine in this response reflect similarities with the prototype phenylethylamine stimulant, amphetamine. It is important to note that these parameters are frequently associated with rewarding aspects of drugs and drug abuse. Additionally, the behavioral profiles of MDMA and I E share certain characteristics with hallucinogen-Iike agents. This unique mixture of stimulus properties and neurochemical actions may contribute to a dangerous behavioral toxicity and neurotoxic potential for drugs like MDMA. 

Outpatient group members were very similar to the inpatient PCP abusers in most sociodemographic and drug-use characteristics. Their mean age was 29 years, educational level 12.6 years, and number of prior arrests 1.5. The majority of outpatients were black (83 percent), unmarried (67 percent), and unemployed (67 percent). Their mean duration of PCP use was almost 8 years, with, usually, no prior or recent substance abuse treatment. Thirty-seven percent used PCP at least daily, always by smoking. Like the inpatient PCP abusers, outpatients frequently (87 percent) reported abuse of other drugs alcohol (46 percent), marijuana (46 percent), and cocaine (37 percent). Several outpatients for whom cocaine was the preferred drug of abuse used PCP as a "cheaper high" when cocaine was not affordable. 

As noted above, considerable research is ongoing to define the overall ideal structural and physicochemical characteristics of drug-like chemical matter. These evolving characteristics should be taken seriously in the context of compound collection design. 

The incorporation of fluorine into a molecule has been widely used to alter the pharmacokinetic properties and overall drug-like properties of compounds. This includes affecting the metabolism, oral absorption, and brain penetration of these molecules [18]. Metabolism can be affected by addition of fluorine directly at or adjacent to the site of metabolism. In addition, substitution with fluorine can increase the lipophilicity of compounds which has been shown to dramatically affect both oral absorption and brain penetration. Finally, the electron-withdrawing characteristic of fluorine has been exploited to lower the P-gp liability of compounds and modulate the pKa of adjacent groups which resulted in increased brain exposure. In the following section, representative examples will highlight the powerful nature of fluorine to modulate overall drug-like properties. 

To test this possibility, they first examined the effect of phosphorofluoridates on isolated rabbit s intestine. On such a preparation the action of drugs, like acetylcholine, which act directly on the muscle differs characteristically from the action of those, like eserine, which act by inhibition of cholinesterase activity. The directly acting drugs produce an immediate contraction which proceeds rapidly to a maximum, and after the drug has been washed out the muscle again quickly relaxes. The contraction produced by cholinesterase-inhibiting drugs, such as... 

Partly due to the limited throughput of Caco-2 permeability measurements, the structure-activity evaluation of compounds tested in the hit-to-lead phase is done with minimal permeability information, at best. Given the importance of membrane permeability in drug absorption, early consideration of the permeability characteristics of hit compounds would enhance the drug-like quality, and ultimately the probability of success, of selected lead candidates. To incorporate permeability information into the hit-to-lead phase of the drug discovery process it is necessary that permeability measurements be made quickly and with small amounts of material. Thus, efforts have been made to automate and miniaturize the Caco-2 permeability assay. 

The ability of the reagent to work in good yield in a wide variety of drug-like molecules-this is a characteristic highly valued by medicinal chemists. 

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