Unknown

Dataset Information

0

In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin.


ABSTRACT: Platensimycin (PTM) and platencin (PTN), two natural products and promising drug leads that target bacterial and mammalian fatty acid synthases, are known to have unfavorable pharmacokinetic properties. It is not clear, however, what the metabolic fates of PTM and PTN are and no efforts have been reported to address this key roadblock in the development of these compounds as viable drug options. Here we describe the pharmacokinetics of PTM and PTN, and reveal rapid renal clearance as the primary metabolic liability with three additional sites of chemical liability: (i) amide hydrolysis, (ii) glucuronidation, and (iii) oxidation. We determined that hydrolysis is a viable clearance mechanism in vivo and synthesized two PTM analogues to address in vivo hydrolysis. Urea- and carbamate-PTM analogues showed no detectable hydrolysis in vivo, at the expense of antibacterial activity, with no further improvement in systemic exposure. The antibacterial sulfur-containing analogues PTM D1 and PTM ML14 showed significant decreases in renal clearance. These studies set the stage for continued generation of PTM and PTN analogues in an effort to improve their pharmacokinetics while retaining or improving their biological activities.

SUBMITTER: Dong LB 

PROVIDER: S-EPMC5421316 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

altmetric image

Publications

In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin.

Dong Liao-Bin LB   Rudolf Jeffrey D JD   Lin Li L   Ruiz Claudia C   Cameron Michael D MD   Shen Ben B  

Bioorganic & medicinal chemistry 20170216 6


Platensimycin (PTM) and platencin (PTN), two natural products and promising drug leads that target bacterial and mammalian fatty acid synthases, are known to have unfavorable pharmacokinetic properties. It is not clear, however, what the metabolic fates of PTM and PTN are and no efforts have been reported to address this key roadblock in the development of these compounds as viable drug options. Here we describe the pharmacokinetics of PTM and PTN, and reveal rapid renal clearance as the primary  ...[more]

Similar Datasets

| S-EPMC5048679 | biostudies-literature
| S-EPMC5410400 | biostudies-literature
| S-EPMC2663125 | biostudies-literature
| S-EPMC2669665 | biostudies-literature
| S-EPMC5063666 | biostudies-literature
| S-EPMC6545883 | biostudies-literature
| S-EPMC3158216 | biostudies-literature
| S-EPMC6072473 | biostudies-literature
| S-EPMC7144934 | biostudies-literature
| S-EPMC7105086 | biostudies-literature