Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481

Abstract

A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce the bicyclic pyrimidine γ-secretase modulator BMS-932481. The compound showed robust reductions of Aβ_1-42 and Aβ_1-40 in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-secretase modulator mechanism, increases in Aβ_1-37 and Aβ_1-38 were observed, with no change in the total amount of Aβ_1-x produced. No Notch-based toxicity was observed, and the overall preclinical profile of BMS-932481 supported its further evaluation in human clinical trials.

Figure 1

Novel triazine/pyrimidine γ-secretase modulators.

Figure 2

Effect of 4 on Aβ species in cultured H4-APPsw cells. See ref (8), Figure 3 for the general method, and ref (16), Figure 1 for additional data.

Scheme 1. Initial Synthesis of Compound 3

Reagents and conditions: (a) PhMgBr, THF, 0 °C to rt, 30 min, then reflux, 2 h; (b) 6 N HCl, 100%; (c) 1:4 30% H₂O₂/HCO₂H, 40 °C, 15 min, then add 1-phenylcyclopentene, rt, 4 h [Caution!: initial exotherm], 84%; (d) N-(chlorocarbonyl)isocyanate, 58 °C, 1 h, then 130 °C, 45 min, 13%; (e) conc. NH₃, 100 °C in sealed tube, 5 h, 100%; (f) POCl₃, 110 °C, microwave, 1 h, 72%; (g) MeNH₂, THF, rt, 69%; (h) 1:1 THF/HOAc, 75 °C, 47%, then separate enantiomers; (i) 4-chloro-1H-imidazole, KOH, DMSO, 80 °C, 20 h, 42%; (j) Fe, 1:2 HOAc/EtOH, 100 °C, 30 min, 97%.

Scheme 2. Medicinal Chemistry Synthesis of Compound 4

Reagents and conditions: (a) ethyl-4-bromobutanoate, DMF, Cs₂CO₃, 60 °C, 72 h, 37%; (b) NaHMDS, THF, 0 °C to rt, 2 h, 94%; (c) urea, 150 °C, then add ketoester, 16 h, 35%; (d) POCl₃, N,N-diethylaniline, 103 °C, 4 h, 77%; (e) MeNH₂, THF, 2 h, 84%; (f) H₂SO₄, NMP, 100 °C, 18 h, 66%, then separate enantiomers; (g) 3-methyl-1H-1,2,4-triazole, KOH, DMSO, 80 °C, 6 h, 26%; (h) H₂, Pd/C, MeOH, 94%.