Synthesis of the GPR40 Partial Agonist MK-8666 through a Kinetically Controlled Dynamic Enzymatic Ketone Reduction

Hyde, Alan M.; Liu, Zhijian; Kosjek, Birgit; Tan, Lushi; Klapars, Artis; Ashley, Eric R.; Zhong, Yong‐Li; Alvizo, Oscar; Agard, Nicholas J.; Liu, Guiquan; Gu, Xiuyan; Yasuda, Nobuyoshi; Limanto, John; Huffman, Mark A.; Tschaen, David M.

doi:10.1021/acs.orglett.6b02910

Cited by 31 publications

(19 citation statements)

References 30 publications

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“…Rats were dosed via oral gavage (PO) at a volume of 5 ml/kg daily at approximately 12:30 PM with either vehicle (0.5% methylcellulose), AP1 at 30 mg/kg, or AP3 at 30 mg/kg. MK-8666, a GPR40 partial agonist synthesized at Merck & Co., Inc., Kenilworth, NJ USA [ 13 ], at 30 mg/kg was administered in feed (Research Diets, New Brunswick, NJ) and provided ad lib. All compounds were administered to achieve maximal efficacious exposures determined in acute efficacy studies similar to those acute studies described above.…”

Section: Methodsmentioning

confidence: 99%

GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent

et al. 2017

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GPR40 agonists are effective antidiabetic agents believed to lower glucose through direct effects on the beta cell to increase glucose stimulated insulin secretion. However, not all GPR40 agonists are the same. Partial agonists lower glucose through direct effects on the pancreas, whereas GPR40 AgoPAMs may incorporate additional therapeutic effects through increases in insulinotrophic incretins secreted by the gut. Here we describe how GPR40 AgoPAMs stimulate both insulin and incretin secretion in vivo over time in diabetic GK rats. We also describe effects of AgoPAMs in vivo to lower glucose and body weight beyond what is seen with partial GPR40 agonists in both the acute and chronic setting. Further comparisons of the glucose lowering profile of AgoPAMs suggest these compounds may possess greater glucose control even in the presence of elevated glucagon secretion, an unexpected feature observed with both acute and chronic treatment with AgoPAMs. Together these studies highlight the complexity of GPR40 pharmacology and the potential additional benefits AgoPAMs may possess above partial agonists for the diabetic patient.

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Section: Methodsmentioning

confidence: 99%

GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent

et al. 2017

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“…[9] Examples of enzymatic DK reductions have been reported on b-keto esters or activated ketones with ap K a range of 7-12, [5,10] with the exception of rare reports using native extremophile KREDs at pH 9. [9] Examples of enzymatic DK reductions have been reported on b-keto esters or activated ketones with ap K a range of 7-12, [5,10] with the exception of rare reports using native extremophile KREDs at pH 9.…”

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confidence: 99%

Synthesis of Vibegron Enabled by a Ketoreductase Rationally Designed for High pH Dynamic Kinetic Reduction

Kosjek

Cabirol

et al. 2018

Angew Chem Int Ed

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“…25 MK-8666, a carboxylic acid containing GRP40 partial agonist closely related to fasiglifam, was shown to markedly improve glycemic control via a mechanism of stimulating insulin secretion in a glucose-dependent manner with minimal risk of hypoglycemia 26 and was under development for the treatment of type 2 diabetes mellitus. 27,28 However, the phase I clinical trial of MK-8666 was terminated due to concerns about its liver safety. A 53-year-old subject in the 150-mg cohort demonstrated increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) above baseline prior to dosing on Day 3 and showed an upward trend on continued dosing.…”

Section: ■ Introductionmentioning

confidence: 99%

Bioactivation of GPR40 Agonist MK-8666: Formation of Protein Adducts in Vitro from Reactive Acyl Glucuronide and Acyl CoA Thioester

Shang

Tschirret-Guth

Cancilla

et al. 2019

Chem. Res. Toxicol.

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MK-8666, a selective GPR40 agonist developed for the treatment of type 2 diabetes mellitus, was discontinued in phase I clinical trials due to liver safety concerns. To address whether chemically reactive metabolites played a causative role in the observed drug induced liver injury (DILI), we characterized the metabolism, covalent binding to proteins, and amino acid targets of MK-8666 in rat and human hepatocytes or cofactor-fortified liver microsomes. MK-8666 was primarily metabolized to an acyl glucuronide in hepatocytes of both species and a taurine conjugate in rat hepatocytes. Similar levels of covalent binding to proteins were observed in rat and human hepatocytes following incubation with [ 3 H]MK-8666. After protease digestion of hepatocyte pellets, amino acid adducts A1, A2, and A3 were identified as transacylated products with lysine, serine, and cysteine residues, respectively. Amino acid adducts A4a−c were identified as glycation adducts resulting from rearrangement of MK-8666−1-O-β-acyl glucuronide to ring-opened aldehydes which further condensed with lysine residues of proteins into imine adducts. Adducts A1−A3 and A4a−c were detected in rat and human liver microsomes fortified with UDPGA. Adducts A1−A3 were detected in rat and human liver microsomes fortified with CoA and ATP. Additionally, a trace amount of CoA thioester metabolite of MK-8666 and its transacylated GSH adduct were detected in human liver microsomes fortified with CoA, ATP, and GSH. Higher levels of covalent binding to protein were observed when [ 3 H]MK-8666 was incubated in liver microsomes supplemented with CoA and ATP compared to UDPGA. Addition of GSH attenuated levels of CoA thioester-mediated covalent binding by 41−45%. Collectively, these studies indicated that metabolism of the −COOH moiety of MK-8666 can form a reactive acyl glucuronide and an acyl CoA thioester, which covalently modifies proteins and may represent one causative mechanism of the observed DILI.

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Synthesis of the GPR40 Partial Agonist MK-8666 through a Kinetically Controlled Dynamic Enzymatic Ketone Reduction

Cited by 31 publications

References 30 publications

GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent

GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent

Synthesis of Vibegron Enabled by a Ketoreductase Rationally Designed for High pH Dynamic Kinetic Reduction

Bioactivation of GPR40 Agonist MK-8666: Formation of Protein Adducts in Vitro from Reactive Acyl Glucuronide and Acyl CoA Thioester

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