Discovery of Azetidinyl Ketolides for the Treatment of Susceptible and Multidrug Resistant Community-Acquired Respiratory Tract Infections

Abstract

Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.

Deuterium Isotope Effects on Drug Pharmacokinetics. I. System-Dependent Effects of Specific Deuteration with Aldehyde Oxidase Cleared Drugs

“…On the basis of immunohistochemical localization in the rat and human, AO-containing cells are ubiquitously distributed to many tissues, with different levels of expression in these tissues between human and rat (Moriwaki et al, 1996(Moriwaki et al, , 2001). Species differences in metabolism of various drugs have also been reported for this enzyme (Beedham et al, 1987(Beedham et al, , 1995Kawashima et al, 1999;Schofield et al, 2000;Kitamura et al, 2006;Sahi et al, 2008;Magee et al, 2009;Zhang et al, 2011). However, it is unclear whether the enzyme from different species functions by a common reaction mechanism.…”

Hydralazine As a Selective Probe Inactivator of Aldehyde Oxidase in Human Hepatocytes: Estimation of the Contribution of Aldehyde Oxidase to Metabolic Clearance

“…When left unexamined in drug design, an impact of AO on the clearance (CL) of a new chemical entity can result in an unexpected low exposure in humans. Examples of instances in which human pharmacokinetics were unacceptable because it was not known that AO contributed to a large extent in metabolic clearance before administration to humans include carbazeran (Kaye et al, 1985), zoniporide , N8-(3-chloro-4-fluorophenyl)-N2-(1-methyl-4-piperidinyl)-pyrimido [5,4-d]pyrimidine-2,8-diamine (BIBX 1382) (Dittrich et al, 2002), and a ketolide antibiotic (Magee et al, 2009). It is also possible that AO-generated metabolites could be responsible for toxicity (Diamond et al, 2010).…”

Effect of Structural Variation on Aldehyde Oxidase-Catalyzed Oxidation of Zoniporide

“…Attempts have been made to recognize this liability early in a lead optimization stage and mitigate the potential of AO catalyzed metabolism at this stage. Several reports describing medicinal chemistry strategies to mitigate AO liabilities have been published recently (Magee et al, 2009;Jones et al, 2011;Linton et al, 2011;Tran et al, 2011;Pryde et al, 2012). …”