CPSA Digest 2001

Proceedings -Wednesday, October 10, 2001

WOB1

The Anxieties of HT Lipophilicity Determination:
Plate Formats, Detection, Purity Level and Data Handling

Background:
The majority of new drugs are intended to be administered by the oral route and thus, in the discovery phase, estimating oral absorption characteristics of compounds is an important goal. It has been reported that undesirable ADME properties cause 22-40% of drug candidate failures in Phase II. Oral bioavailability can be determined using animal pharmacokinetic studies but this procedure is time-consuming and not amenable to high throughput required in today's discovery environment. Instead, an in vitro predictive test is more ideal. There have been a few in vitro and cell culture techniques developed in recent years that have helped to rapidly assess intestinal permeability of compounds.

Premise:
It has been proposed that membrane permeability can be predicted for some compounds with reasonable accuracy based solely on physicochemical parameters, before performing any laboratory experiments.

The Lipinski "rule of five" mnemonic introduces numerical values to caution discovery chemists early on. This "rule" states that POOR absorption or permeation is more likely when:

• There are > 5 H-bond donors
• The MW > 500
• The ClogP is > 5 (or MlogP > 4.15)
• The sum of N and O is > 10
  (Substrates and natural transporters are exceptions)

It is well known that efficient oral absorption will occur only after drug has dissolved and presented itself to the intestinal mucosal surface where it can cross the epithelium. Dissolution is determined by the interdependent influences of aqueous solubility, ionizability (pKa), and lipophilicity (octanol/water log P or log D7.4).

Note that logP is a crucial factor governing passive membrane partitioning, influencing permeability opposite to its effect on solubility (i.e., increasing logP enhances permeability while reducing solubility). In light of this counterdependence, it has been suggested that oral absorption may be optimal within a log P range of 0.5 to 2.0.

Experimental (logP minus the computed logP) values were plotted and analyzed for a set of 311 Pfizer compounds, and the data were presented and generalized. Faster throughput procedures for performing these physicochemical determinations for ELOGD were discussed, including the use of custom-developed software macros before, during and after the chromatographic run.

Value of the Technology
The ELOGD tests conducted are currently restricted to basic and neutral compounds. Acidic compounds, currently 5-10% of all submissions, are not amenable to this approach but an alternative method is being sought. These tests are largely automated and take about 20 min per compound. About 270 compounds per week can be analyzed presently. To date, more than 7,000 compounds have been analyzed using this approach. ElogD/ElogP data are being used to train the ACDLabs logP/logD user database.

References
CA Lipinski, F Lombardo, BW Dominy and PJ Feeney, Adv. Drug Deliv. Rev. 23, 3-25 (1997).

CA Lipinski, Drug-like properties and the causes of poor solubility and poor permeability." J Pharm and Tox Methods 44, 235-249 (2000).

RA Scherrer and SM Howard, Use of Distribution Coefficients in Quantitative Structure Activity Relationships. J. Med Chem. 20, 53-58 (1977).

Hansch, C.; Björkroth, J.P.; Leo, A. Hydrophobicity and Central Nervous System Agents: On the Principle of Minimal Hydrophobicity in Drug Design. J. Pharm. Sci. 1987, 76, 663-687.

Dearden, J.C.; Bresnen, G.M. The measurement of Partition Coefficients. Quant. Struct.-Act. Relat. 1988, 7, 133-144.

Tetko, I. V.; Tanchuk, V. Y;Villa, A.E.P. Prediction of n-Octanol/Water Partition Coefficients from PHYSPROP Database Using Artificial Neural Networks and E-State Indices.J. Chem. Inf. Comput. Sci. 2001, 41, 1407-1421.

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