Metabolism of [¹⁴C]GSK977779 in Rats and Its Implication with the Observed Covalent Binding

Abstract

ABSTRACT:GSK977779 is a potent HM74a agonist evaluated for the treatment of dyslipidemia. The disposition and metabolism of [ 14 C]GSK977779 (67.6 mol/kg p.o.) was studied in male and female rats. The compound was well absorbed and its primary route of elimination was in the feces. Based on metabolite profiling of plasma extracts and urine and bile samples, it was demonstrated that GSK977779 was extensively metabolized in the rat by N-dealkylation, mono-and dioxygenation, reductive and oxidative cleavage of the 1,2,4-oxadiazole ring, and conjugative pathways. After plasma extraction high amounts of nonextractable radioactivity were observed, which were more pronounced in female rats. Size-exclusion chromatography and SDS gel electrophoresis indicated that the majority of the nonextractable radioactivity was covalently bound to plasma proteins. Solubilization of the plasma protein pellet followed by high-performance liquid chromatography and mass spectrometry suggested that a carboxylic acid metabolite derived from oxadiazole ring cleavage may be responsible for the observed covalent binding of the radioactivity to rat plasma proteins.

Metabolism and disposition of opicapone in the rat and metabolic enzymes phenotyping

“…The pharmacokinetic profile of opicapone and its metabolites was investigated in healthy subjects demonstrating an approximately linear pharmacokinetics (PK) following single ascending oral doses (10,25,50,100,200, 400, 800, and 1200 mg) 13 and multiple once-daily oral doses. 14 Despite its short apparent terminal elimination half-life (t 1/2 , 0.8-3.2 h), the levels of COMT inhibition in erythrocyte were sustained far beyond the observable point of plasma drug clearance (6-10 h) making it suitable for a once-daily dosage regimen.…”

Mitigating Heterocycle Metabolism in Drug Discovery

“…Also, if the five-membered ring on compound 104 is the site of metabolism, the 1,2,4-oxadiazole ring may undergo metabolic N−O ring-opening, which is precedented in the literature. 13,66 Without an N−O bond, the 1,3,4-oxadiazole ring on 105 would not undergo this route of metabolism. 67 In their work on dipeptidyl peptidase IV (DPP-4) inhibitors for the treatment of type 2 diabetes, Nordhoff et al determined the metabolic stability of a number of three-heteroatom fivemembered heterocycles (Figure 31).…”

“…In their anticancer program, Tsou et al prepared a mammalian target of rapamycin (mTOR) inhibitor containing an aza-bicyclo seven-membered ring (66) (Figure 20). 49 This compound was rapidly metabolized by both phase I and phase II metabolism in MLM.…”

Metabolism of a G Protein-Coupled Receptor Modulator, Including Two Major 1,2,4-Oxadiazole Ring-Opened Metabolites and a Rearranged Cysteine-Piperazine Adduct

“…Metabolism involving 1,2,4-oxadiazole ring-opening has been of interest in the literature (Lan et al, 1973;Gyarmati et al, 1976;Yabuki et al, 1993;Dalvie et al, 2002;Allan et al, 2006;Bateman et al, 2006;Tsalta et al, 2011). The oxadiazole ring can undergo NADPH-dependent reductive cleavage of the N-O bond and then subsequent hydrolysis, to produce various ring-opened products such as amides and carboxylic acids (Scheme 1a) (Lan et al, 1973;Gyarmati et al, 1976;Allan et al, 2006;Tsalta et al, 2011).…”

“…The oxadiazole ring can undergo NADPH-dependent reductive cleavage of the N-O bond and then subsequent hydrolysis, to produce various ring-opened products such as amides and carboxylic acids (Scheme 1a) (Lan et al, 1973;Gyarmati et al, 1976;Allan et al, 2006;Tsalta et al, 2011). It is worth noting that the reductive N-O bond cleavage for the oxadiazole could also occur chemically, e.g., through reaction with ferrous hydroxide (Lan et al, 1973).…”