Received for publication April 15, 2009.
Revised June 18, 2009.
Accepted for publication June 18, 2009.

Modulation of LogD_(7.4) and pK_a to achieve the optimum balance of blood clearance and volume of distribution for a series of tetrahydropyran H₃ antagonists

Abstract

The relationship between the rat pharmacokinetics and the physicochemical parameters, LogD_(7.4) and pK_a were studied for a series of tetrahydropyran (THP) compounds. Sixteen compounds ranging in LogD_(7.4) 0.1 - 1.8 were administered intravenously to rats and the pharmacokinetic parameters determined from blood concentration time curves. Across the series, a weak correlation was observed between LogD_(7.4) and blood clearance, suggesting that LogD_(7.4) values lower than 0.5 were required to prevent clearance at hepatic blood flow. In terms of the volume of distribution, the compounds fell into three distinct sub series characterised by the number of basic centres and differences in ionisation of each basic centre at physiological pH. These were referred to as the monobasic, weak second base and strong second base sub-series. All compounds exhibited volumes of distribution greater than body water, as would be expected from their lipophilic and basic nature. For a given clogP the strong second base sub-series showed higher volumes of distribution than the weak second base sub-series, which in turn exhibited higher values than the monobasic sub-series. In addition, for the weak second base sub-series, volume of distribution could be tuned by modulating the pK_a of the second basic centre. This relationship was rationalized in respect to the interactions of the ionisable centres with phospholipid heads in the cell membrane and/or lysosomal trapping. Compounds in the weak second base sub-series showed optimal volumes of distribution and when combined with a LogD_(7.4) of 0.1, driving to moderate blood clearance, one compound showed the optimal pharmacokinetic profile.

Key words: drug discovery, half-life, pharmacokinetics