Master of Science (MS)
Bioisostere, Carboxylic Acid, Disposition, Tetrazolone
Chemistry; Pharmaceutical sciences
Carboxylic acids are ubiquitous in medicinal compounds, such as nonsteroidal anti-inflammatories, statins, hypertensives, and anticoagulants. Despite their prolific use, unfavorable characteristics such as metabolic instability, poor membrane permeability, and toxicity have been associated with this moiety in some instances. Bioisosteres have been employed to attenuate these issues. However, bioisostere use can alter drug potency and disposition. Recently, our company demonstrated the feasibility of the tetrazolone moiety as a carboxylic acid bioisostere for the angiotensin II antagonist telmisartan. R941000 (telmisartan-tetrazolone analog) was a potent in vitro inhibitor of angiotensin II and possessed a similar disposition to telmisartan. To the best of our knowledge, no studies of the changes in disposition caused by bioisosteric replacement of a carboxylic acid with a tetrazolone have been published. In this work, the disposition of R941000 was evaluated in Sprague Dawley rats, and in vitro metabolism was conducted using human and rat hepatocytes and supplemented microsomes. Results indicated comparable PK parameters for R941000 relative to telmisartan, respectively, bioavailability (64.7% vs 59.2%), exposure (2610 ngL/h vs 1850 ngL/h) Clpred (4.51 ml/min vs 7.23 ml/min) t1/2 (5.37h vs 3.64 h) and Vss (1.67L/kg vs 1.59L/kg). Both compounds underwent biliary excretion, and glucuronide metabolites were found in rat bile; however, no significant glucuronidation was observed in in vitro assays. Additional studies utilizing tetrazolone bioisosteres in other species and classes of compounds are needed to further characterize their utility as a carboxylic acid substitute.
Murray, Ryan Brant, "An Evaluation of the Disposition of R941000, a Tetrazolone-Telmisartan Analog: A Case Study of the Suitability of Tetrazolone As a Carboxylic Acid Bioisostere" (2015). Master's Theses. 4655.