Drug-like property

The various properhes described above are important for drugs, in particular for those given orally. The important question arises whether such properties of drugs 

From an analysis of the key properties of compounds in the World Dmg Index the now well accepted Rule-of-5 has been derived [25, 26]. It was concluded that compounds are most Hkely to have poor absorption when MW 500, calculated octanol-water partition coefficient Clog P 5, number of H-bond donors 5 and number of H-bond acceptors 10. Computation of these properties is now available as a simple but efficient ADME screen in commercial software. The Rule-of-5 should be seen as a qualitative absorption/permeabiHty predictor [43], rather than a quantitative predictor [140]. The Rule-of-5 is not predictive for bioavail-abihty as sometimes mistakenly is assumed. An important factor for bioavailabihty in addition to absorption is liver first-pass effect (metaboHsm). The property distribution in drug-related chemical databases has been studied as another approach to understand drug-likeness [141, 142]. 

In addition, the calculation of many different ID, 2D and 3D descriptors is possible using a range of commercially available software packages, such as Sybyl, Cerius2, Tsar, Molconn-Z and Hybot. Several new descriptor sets are based on quantification of 3D molecular surface properties, and these have been explored for the prediction of, e.g., Caco-2 permeability and oral absorption. It is pointed out here that a number of these new descriptors are strongly correlated to the more traditional physico-chemical properties. 

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In general, there are three milestones for the drug discovery process. The first is the identification of a verified hit series (primary activity in a related series of molecules), the second the determination of a lead series (series with primary activity and drug-like properties), and the third a clinical candidate (activity, positive pharmaceutical, and pharmacokinetic properties devoid of toxicity). An example... 

Lipinski, C. A. (2000). Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Tox. Meth. 44 235-249. 

Lipinski CA. Drug-like properties and the causes of poor solubility and poor... 

Lipinski, C.A. (2000) Drug-like Properties of Poor Solubility and Poor Permeability. Journal of Pharmacological and Toxicological Methods, 44(1), 235-249. 

Leeson, P. D., Davis, A. D., Steele, J. Drug-like properties guiding principles for design - or chemical prejudice ... 

When assayed in HEK293 cells transfected with the cloned human, rat and guinea pig TRPVl, (23a) showed similar potencies. Not unexpeetedly, (23a) showed poor metabolic stability and a structure-activity study to optimize potency and drug-like properties was initiated. Modification on the left-handed A -aryl section showed that ... 

At the hit triage stage, it is most common to be able to characterize sets of compounds in a kinetic solubility assay. In the assessment and utilization of these data, the potential disconnects between kinetic and thermodynamic solubility must be considered. Low kinetic solubility for a series of compounds should lead a project team to be concerned about the behavior of compounds in biological assays and buffers, as well as the potential for optimizing drug-like properties in that series. Conversely, while high kinetic solubility is a desirable property, chemists should still remain cognizant of the need to assess thermodynamic solubility as compounds are further optimized. 

EFFECTS OF FLUORINE ON PHARMACOKINETIC PARAMETERS AND DRUG-LIKE PROPERTIES... 

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. 

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