2016
DOI: 10.1021/acs.orglett.6b02910
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Synthesis of the GPR40 Partial Agonist MK-8666 through a Kinetically Controlled Dynamic Enzymatic Ketone Reduction

Abstract: A scalable and efficient synthesis of the GPR40 agonist MK-8666 was developed from a simple pyridine building block. The key step to set the stereochemistry at two centers relied on an enzymatic dynamic kinetic reduction of an unactivated ketone. Directed evolution was leveraged to generate an optimized ketoreductase that provided the desired trans alcohol in >30:1 dr and >99% ee. Further, it was demonstrated that all four diastereomers of this hydroxy-ester could be prepared in high yield and selectivity. Sub… Show more

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Cited by 31 publications
(19 citation statements)
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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%
“…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%
“…[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.…”
mentioning
confidence: 99%
“…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%