MK-8245

2 years -80 in solvent

Orally

A Phase I trial to study the safety, tolerance, pharmacokinetics, and glucose lowering activity of MK8245 in patients with Type 2 diabetes has been completed.

Suspended in 1% methocel in saline

MK-8245, a phenoxy piperidine isoxazole derivative, has been identified as a potent and liver-specific SCD inhibitor. It contains a tetrazole acetic acid moiety, which is the key molecule for OATPs recognition and liver-targeting. MK-8245 displays similar potencies against human, rat and mouse SCD1 with IC50 values of 1 nM for human SCD1 and 3 nM for both rat SCD1 and mouse SCD1. MK-8245 exhibits a significant SCD inhibition in the rat hepatocyte assay which contains functional, active OATPs with IC50 of 68 nM, while being only weakly active in the HepG2 cell assay which is devoid of active OATPs with IC50 of ca.1 uM. MK-8245 displays highly selective activity for the delta-5 and delta-6 desaturases (i.e., >100000 uM vs rat and human delta5D and delta6D as assessed in the HepG assay. [1]

SCD1 enzyme activity assay, The potency of MK-8245 against the stearoyl-CoA desaturase is determined by measuring the conversion of radiolabeled stearoyl-CoA to oleoyl-CoA using rat liver microsome or human SCDl (hSCD-1). Liver microsome is prepared from male Wistar or Spraque Dawley rats on a high carbohydrate diet for 3 days. The livers are homogenized (1 :10 w/v) in a buffer containing 250 mM sucrose, 1 mM EDTA, 5 mM DTT and 50 mM Tris-HCl (pH 7.5). After a 100, 000 x g centrifugation for 60 minutes, the liver microsome pellet is suspended in a buffer containing 100 mM sodium phosphate, 20% glycerol, 2 mM DTT and stored at -78 C. The human SCDl desaturase system is reconstituted using human SCDl from a baculovirus/Sf9 expression system, cytochrome B5 and cytochrome B5 reductase. Typically, different concentrations of MK-8245 in 2 uL DMSO is incubated for 15 minutes at room temperature with 180 uL of the SCD enzyme in a buffer containing 100 mM Tris-HCl (pH 7.5), ATP (5 mM), Coenzyme-A (0.1 mM), Triton X-100 (0.5 mM) and NADH (2 mM). The reaction is initiated by the addition of 20 uL of [3H]-stearoyl-CoA (final concentration = 2 uM, radioactivity concentration = 1 uCi/mL). After 10 minutes, the reaction mixture (80 uL) is mixed with a calcium chloride/charcoal aqueous suspension (100 uL charcoal (10% w/v) plus 25 uL CaCl2 (2N). After centrifugation to precipitate the radioactive fatty acid species, tritiated water released from 9, 10-[3H]-stearoyl-CoA by the SCD enzyme is quantified on a scintillation counter.

MK-8245 is an liver-targeting inhibitor of stearoyl-CoA desaturase (SCD) with IC50 of 1 nM for human SCD1 and 3 nM for both rat SCD1 and mouse SCD1, with anti-diabetic and anti-dyslipidemic efficacy. Phase 2.

MK-8245 is a potent SCD inhibitor in the liver but does not affect the SCD enzyme in the skin and eye tissues like other systemically distributed SCD inhibitors.