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. 2011 Aug 5;2(10):786-91.
doi: 10.1021/ml200175q. eCollection 2011 Oct 13.

Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator

Hairuo Peng  1 , Tina Talreja  1 , Zhili Xin  1 , J Hernan Cuervo  1 , Gnanasambandam Kumaravel  1 , Michael J Humora  1 , Lin Xu  1 , Ellen Rohde  1 , Lawrence Gan  1 , Mi-Young Jung  1 , Melanie N Shackett  1 , Sowmya Chollate  1 , Anthone W Dunah  1 , Pamela A Snodgrass-Belt  1 , H Moore Arnold  1 , Arthur G Taveras  1 , Kenneth J Rhodes  1 , Robert H Scannevin  1
Affiliations

Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator

Hairuo Peng et al. ACS Med Chem Lett. .

Abstract

We have investigated a novel series of acid-derived γ-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which lowered Aβ42, increased Aβ38, but had little to no effect on Aβ40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain Aβ42 levels in CF-1 mice and Fischer rats, as well as plasma Aβ42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.

Keywords: Alzheimer's; GSM; Mannich reaction; Secretase; amyloid.

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Figures

Figure 1
Figure 1
Structures of GSMs.
Figure 2
Figure 2
Structures of early lead 5 and BIIB042.
Scheme 1
Scheme 1. Synthesis of Compound 10a
(a) BnBr, K2CO3, acetonitrile, room temperature, 6 h, 87%. (b) LiHMDS, THF, CH3I, −78 °C to room temperature, 76%. (c) Pd/C, H2, MeOH, 3 h, 87%. (d) 4-Fluorobenzaldehyde, 4-methylpiperidine, trifluoro toluene, microwave, 120 °C, 1 h, 42%. (e) Tf2O, pyridine, CH2Cl2, 75%. (f) 4-(Trifluoromethyl)phenyl boronic acid, Pd(PPh3)4, 1,2-dimethoxyethane/ethanol/saturated Na2CO3, microwave, 120 °C, 0.5 h, 67%. (g) NaOH, MeOH/THF (1:1), microwave, 100 °C, 10 min, 86%. (h) SCF chiral separation, Chiralpak AD-H (2 cm × 15 cm), 10% isopropanol (0.1% DEA)/CO2, 100 bar, 60 mL/min, 220 nm.
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