Impact of Physicochemical and Structural Properties on the Pharmacokinetics of a Series of α1_L-Adrenoceptor Antagonists

Abstract

ABSTRACT:A rational drug discovery process was initiated to design a potent and prostate-selective ␣1 L -adrenoceptor antagonist with pharmacokinetic properties suitable for once a day administration after oral dosing, for the treatment of benign prostatic hyperplasia. Two series of compounds based on a quinoline or quinazoline template were identified with appropriate pharmacology. A series of high molecular weight cations with high hydrogen-bonding potential had extensive in vivo clearance, despite demonstrating metabolic stability. Studies in the isolated perfused rat liver and fresh rat hepatocytes indicated that active transport protein-mediated hepatobiliary elimination is an efficient clearance process for these compounds. A reduction in molecular weight and hydrogen-bonding potential resulted in a second series of compounds with in vivo hepatic clearance predictable from in vitro metabolic clearance. Initially, lipophilicity was reduced within this second series to reduce metabolic clearance and increase elimination half-life. However, this strategy also resulted in a concomitant reduction in volume of distribution and a negligible effect on prolonging half-life. An alternative strategy was to increase the intrinsic metabolic stability of the molecule by careful structural modifications while maintaining lipophilicity. Replacement of the metabolically vulnerable morpholine side chain resulted in identification of UK-338,003, (N-[2-(4-amino-6,7-dimethoxy-5-pyridin-2-yl-quinazolin-2-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-methanesulfonamide), which fulfilled the objectives of the discovery program with suitable pharmacology (human prostate ␣1 L pA 2 of 9.2 with 25-fold selectivity over rat aorta ␣1 D ) and sufficiently long elimination half-life in human volunteers (11-17 h) for once a day administration.␣1-Adrenoceptor antagonists are well precedented in the effective treatment of both hypertension and benign prostatic hyperplasia (BPH); e.g., doxazosin (Fulton et al., 1995), terazosin (Jonler et al., 1994), and tamsulosin (Wilde and McTavish, 1996). However, because many of the ␣1-adrenoceptor antagonists clinically used in the treatment of BPH were originally developed for hypertension, they are nonselective for ␣1-adrenoceptor subtypes. These nonselective ␣1-adrenoceptor antagonists have similar efficacy and are generally well tolerated in BPH patients, but some patients experience dizziness and postural hypotension, which may be minimized by dose titration. It has been postulated that a drug that blocks the ␣1 L -adrenoceptor subtype would specifically target the prostate and thus have a better ratio of efficacy to safety, with fewer cardiovascular side effects than currently available nonselective ␣1-adrenoceptor antagonists.The aim of the drug discovery program was to identify a novel and potent ␣1 L -adrenoceptor antagonist that was functionally selective for the prostate gland over the cardiovascular system and thus have the potential to be effective in the treatment of BPH with fewer dose-limiti...

Pharmacokinetics of betamethasone and betamethasone 17-monopropionate in Chinese healthy volunteers after intramuscular injection of betamethasone phosphate/betamethasone dipropionate

“…The initialapparentv olume of distribution (V d /F)i s sometimesareflection of howadrugwill distribute throughout the bodydepending on theirphysicochemicalp roperties,e. g. solubility,c harge,size,etc [ 13].The V d /Fof BOH observed in thisstudywas207.5 -83.4 L, indicating ane xtensived istribution of BOH.Thisw asdue partlytothe relativehigh lipophilicity of BOH, whichassured its easy permeation across the cell membrane. The unusuallylarge V d /Fof B17P(2352.7 -429.4 L),which wasacquired undert he assumption thatall BDP was converted toB17P, drewour attention.…”

Investigation of Regional Mechanisms Responsible for Poor Oral Absorption in Humans of a Modified Release Preparation of the α-Adrenoreceptor Antagonist, 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (UK-338,003): The Rational Use of ex Vivo Intestine to Predict in Vivo Absorption

“…UK-388,003 is metabolized almost exclusively by CYP3A in humans (Betts et al, 2007), which is localized primarily in the upper GI tract with much lower levels in distal gut (McKinnon et al, 1995). In rodents, UK-388,003 is metabolized exclusively by CYP2C, which has overlapping substrate specificity with CYP3A4 (Betts et al, 2007). Given the evidence for good permeability in the upper intestine, it seems unlikely that gut wall metabolism will be an important factor in reducing UK-388,003 permeability in the distal gut.…”

The evolution of the OATP hepatic uptake transport protein family in DMPK sciences: from obscure liver transporters to key determinants of hepatobiliary clearance

“…As a result, the project focus shifted to investigation of lower molecular weight (<510) quinoline or quinazoline compounds for which metabolism was the predominant clearance route. Ultimately this yielded two compounds, which were progressed to clinical investigation, with good pharmacological potency and selectivity and acceptable oral pharmacokinetic properties: UK-294,315 (Harrison et al, 2004) and UK-338,003 (Betts et al, 2007).…”

“…Thus a drug discovery programme was initiated at Pfizer with the aim to design a novel and potent α1 L -adrenoceptor antagonist that was functionally selective for the prostate gland over the cardiovascular system, with pharmacokinetic properties suitable for once a day administration after oral dosing, for the treatment of BPH. The first series of compounds investigated was a series of lipophilic bases with large 2-and 4-substituents on a core quinoline or quinazoline ring template (Betts et al, 2007). These compounds were exemplified by UK-191,005, which was a weak base with a log D 7.4 of 4, high molecular weight (609) and a high propensity for hydrogen bonding.…”