Background LY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment of tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. Herein, we report on nonclinical and clinical studies that assessed the effect of LY3372689 on brain OGA enzyme occupancy (EO). Method Brain OGA EO of LY3372689 was measured in the frontal cortex of rats using tracer LSN3291920, a non‐fluorinated analog of a positron emission tomography (PET) radioligand 18F‐ LY3316612. A single oral dose study in healthy volunteers (HV) utilizing18F‐LY3316612 is ongoing to assess brain OGA EO of LY3372689 (NCT03944031). The study consists of up to 5 Cohorts (N = 3 – 6 subjects per Cohort). Upon completion, each subject will have participated in one cohort and have received a baseline PET scan and up to two post‐dose PET scans. In the initial cohorts, the post‐dose PET scans were conducted at approximately 2 and 24 hours after LY3372689 administration. The study design is adaptive to allow adjustment of the LY3372689 dose, timing of PET scans and pharmacokinetic samples, and number of subjects, pending results of prior cohorts. Result In rat studies, LY3372689 demonstrated a dose‐dependent change in OGA EO following a single oral dose with a maximum EO of greater than 90%. In the human PET study, a total of 12 healthy volunteers across 3 dose cohorts (N = 4 HV per cohort) have been enrolled to date. A plasma concentration‐dependent increase in brain OGA EO was observed with EO exceeding 90% at 24 hours following the highest dose of LY3372689 administered. Conclusion Non‐clinical and clinical EO studies demonstrated that occupancy of the OGA enzyme effectively translated from rats to humans after single doses of LY3372689. The human PET data can be used to support LY3372869 dose selection for efficacy trials in tauopathies.

A procedure for tert-butoxycarbonyl (Boc) group removal using concentrated HCl and acetone was developed and utilized on multi-kilogram scale in the synthesis of LY544344·HCl (1). The details surrounding this procedure and the advantages offered by it are described herein.

Background LY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment for tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. Herein we report the first clinical study that assessed safety and pharmacokinetics (PK) of LY3372689 after single oral doses in healthy volunteers (HV). Method The phase 1 clinical trial (NCT03819270) was a single ascending dose, randomized, crossover, placebo controlled, investigator‐ and subject‐blind study. Each HV received up to 3 escalating single doses of LY3372689 or placebo over 3 study periods with an approximately 7‐day follow‐up period after each dose, such that a total of 6 LY3372689 dose levels were evaluated. Safety was assessed by adverse events (AE), safety laboratories, electrocardiograms, vital signs, physical exams, and neurological exams. Plasma PK was assessed up to 48 hours after LY3372689 administration. Result A total of 23 HV (15 males, 8 females; 22 – 63 years) participated in the study, of which 18 completed and 5 did not complete due to loss to follow up procedures or did not meet randomization criteria. LY3372689 was generally well tolerated up to the maximum dose administered. There were no serious AE reported and no subjects discontinued the study because of an AE. A total of 13 treatment‐emergent AE reported by 5 subjects considered as possibly related to study treatment were mostly mild in severity, and included pain of skin, headache, limb discomfort, pain in extremity, chest discomfort, muscle fatigue, nausea, and rash macular. The PK of LY3372689 supported daily dosing and was generally dose proportional based on AUC and Cmax. Conclusion LY3372689 demonstrated an acceptable safety and PK profile following single oral doses of LY3372689 in HV, which supports further investigation of LY3372689 as a potential treatment for tauopathies.

This article describes the use of tetramethylammonium fluoride tetrahydrate (TMAF·4H2O) for the large-scale preparation of a challenging 4-fluorothiazole. Commercially available TMAF·4H2O was procured on a large scale and rigorously dried by distillation with isopropyl alcohol and then dimethylformamide at elevated temperature. This method of drying provided anhydrous TMAF [TMAF (anh)] containing <0.2 wt % water and <60 ppm isopropanol. The use of TMAF (anh) was essential for production of the 4-fluorothiazole. When the chlorothiazole starting material was treated with other anhydrous fluoride sources, poor conversion of the starting material or potential safety issues were observed. SNAr fluorination using dried TMAF·4H2O was carried out at a 45.1 kg scale at 95–100 °C to produce 36.8 kg of 4-fluorothiazole 1b.

The novel preparation of 2-aminopyridoimidazoles and 2-aminobenzimidazoles via the cyclization of (2-aminopyridin-3-yl)urea and (2-aminophenyl)urea substrates in the presence of phosphorus oxychloride is described. This methodology is demonstrated for a range of urea substrates with aminoimidazole products obtained in good yields and with excellent levels of purity.