Modulation of the Partition Coefficient between Octanol and Buffer at pH 7.4 and pK_ato Achieve the Optimum Balance of Blood Clearance and Volume of Distribution for a Series of Tetrahydropyran Histamine Type 3 Receptor Antagonists

Abstract

ABSTRACT:The relationship between rat pharmacokinetics and physicochemical parameters [the partition coefficient between octanol and buffer at pH 7.4 (log D (7.4) ) and pK a ] was studied for a series of tetrahydropyran compounds. Sixteen compounds ranging in log D (7.4) 0.1 to 1.8 were administered intravenously to rats, and the pharmacokinetic parameters were determined from blood concentration time curves. Across the series, a weak correlation was observed between log D (7.4) and blood clearance, suggesting that log D (7.4) values less than 0.5 were required to prevent clearance at hepatic blood flow. In terms of the volume of distribution (V d ), the compounds fell into three distinct subseries characterized by the number of basic centers and differences in ionization of each basic center at physiological pH. These were referred to as the monobasic, weak second base, and strong second base subseries. All the compounds exhibited V d greater than body water, as would be expected from their lipophilic and basic nature. For a given clog P, the strong second base subseries showed higher V d than the weak second base subseries, which in turn exhibited higher values than the monobasic subseries. In addition, for the weak second base subseries, V d could be tuned by modulating the pK a of the second basic center. This relationship was rationalized in respect to the interactions of the ionizable centers with phospholipid heads in the cell membrane and/or lysosomal trapping. Compounds in the weak second base subseries showed optimal V d , and when combined with a log D (7.4) of 0.1, driving to moderate blood clearance, one compound showed the optimal pharmacokinetic profile.The optimization of absorption, distribution, metabolism, and excretion properties and prediction of human pharmacokinetics have become important parts of the early selection process in drug discovery. It is well known that the physicochemical properties of a molecule (lipophilicity, molecular weight, hydrogen bonding potential, and pK a ) influence the pharmacokinetic profile of a molecule, and the desirable absorption, distribution, metabolism, and excretion properties have been defined (Smith, 2001;van De Waterbeemd et al., 2001). In this article, we describe how the modulation of lipophilicity and pK a within a series of tetrahydropyran (THP) histamine type 3 receptor (H 3 ) antagonists was used to optimize rat pharmacokinetic parameters and to select an appropriate compound for further progression.The objective of the H 3 antagonist program was to rapidly accelerate a candidate compound to proof-of-concept studies in allergic rhinitis. For the disease target in question, an orally administered compound with a once/twice-daily dosing regimen was key to development. Neither central nervous system penetration nor central nervous system exclusion was requisite in the candidate as the site of action was peripheral. In-house medicinal chemistry resulted in the identification of a number of potent H 3 antagonists containing a THP core (Figs. 1 and 2)...

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