gamma-Secretase Modulators

Oxadiazine is a potent modulator of γ-secretase with Aβ42 IC50 value of 11 nM and Aβtotal/ Aβ42 value of 1170.[1]
γ-Secretase is one of intramenbrane-cleaving aspartyl protease which cleaves many type-I membrane proteins and many of them have important biological functions.γ-secretase is responsible for the generation Aβfrom the amyloid precusor protein.γ-Secretase has been considered as an important drug target for Alzheimer's disease.γ-Secertase also is responsible for Notch processing which is related to cancer such as leukemia.
Oxadiazine is one analogues of BMS-869780 which is anotherγ-secretase modulator. It showed a four folds separation between the IC 50 of Aβ42 and Aβ40 H4-APPsw cells which overexpress APP protein. It also increase Aβ37 and Aβ38 levels whereas decrease Aβ42 and Aβ40 level. It also has little effect on APP-CTFα and no effect on APP-CTFβ and notch processing. It can significantly decrease Aβ42 and Aβ40 level in rat brain and plasma.[1, 2]
References:
[1].    Huang X, Zhou W, Liu X, Li H, Sun G, Mandal M, Vicarel M, Zhu X, Bennett C, McCraken T et al: Synthesis and SAR Studies of Fused Oxadiazines as gamma-Secretase Modulators for Treatment of Alzheimer's Disease. ACS Med Chem Lett, 3(11):931-935.
[2].    Toyn JH, Thompson LA, Lentz KA, Meredith JE, Jr., Burton CR, Sankaranararyanan S, Guss V, Hall T, Iben LG, Krause CM et al: Identification and Preclinical Pharmacology of the gamma-Secretase Modulator BMS-869780. Int J Alzheimers Dis, 2014:431858.

Discovery of novel 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives as gamma-secretase modulators (Part 2).[Pubmed:27255179]

Bioorg Med Chem. 2016 Jul 15;24(14):3192-206.

gamma-Secretase Modulators (GSMs), which lower pathogenic amyloid beta (Abeta) without affecting the production of total Abeta or Notch signal, have emerged as a potential therapeutic agent for Alzheimer's disease (AD). A novel series of 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives was discovered and characterized as GSMs. Optimization of substituents at the 8-position of the core scaffold using ligand-lipophilicity efficiency (LLE) as a drug-likeness guideline led to identification of various types of high-LLE GSMs. Phenoxy compound (R)-17 exhibited especially high LLE as well as potent in vivo Abeta42-lowering effect by single administration. Furthermore, multiple oral administration of (R)-17 significantly reduced soluble and insoluble brain Abeta42, and ameliorated cognitive deficit in novel object recognition test (NORT) using Tg2576 mice as an AD model.

Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme.[Pubmed:27426299]

Bioorg Med Chem Lett. 2016 Aug 15;26(16):3928-37.

The design and construction of a series of novel aminothiazole-derived gamma-Secretase Modulators is described. The incorporation of heterocyclic replacements of the terminal phenyl D-ring of lead compound 1 was conducted in order to align potency with favorable drug-like properties. gamma-Secretase modulator 28 displayed good activity for in vitro inhibition of Abeta42, as well as substantial improvement in ADME and physicochemical properties, including aqueous solubility. Pharmacokinetic evaluation of compound 28 in mice revealed good brain penetration, as well as good clearance, half-life, and volume of distribution which collectively support the continued development of this class of compounds.

Analyzing Amyloid-beta Peptide Modulation Profiles and Binding Sites of gamma-Secretase Modulators.[Pubmed:28065262]

Methods Enzymol. 2017;584:157-183.

gamma-Secretase is a key player in the pathogenesis of Alzheimer's disease (AD). The intramembrane-cleaving enzyme initially cleaves a C-terminal fragment of the amyloid precursor protein (APP) at the varepsilon-site within its transmembrane domain to release the APP intracellular domain. Subsequent stepwise carboxy-terminal trimming cleavages eventually release amyloid-beta (Abeta) peptides of 37-43 amino acids into the extracellular space. Abeta42 as well as the much less abundant Abeta43 species are highly aggregation prone and can deposit as plaques in the brains of affected patients, which are widely believed to be causative of AD. Disappointingly, due to lack of efficacy and side effects likely attributable to the inhibition of the crucial substrate Notch, inhibitors of gamma-secretase that lower Abeta generation failed in clinical trials of AD. There is hope, however, that recently developed potent gamma-Secretase Modulators (GSMs) provide a safer approach for disease modification. These compounds have the unique property of primarily shifting the generation of Abeta42 toward that of shorter peptides without affecting the varepsilon-site cleavage of Notch and other substrates. In this chapter, we describe methods to investigate how GSMs affect the activity of the enzyme as well as how their molecular targets are identified.

Design, Synthesis, and Evaluation of a Novel Series of Oxadiazine Gamma Secretase Modulators for Familial Alzheimer's Disease.[Pubmed:28230986]

J Med Chem. 2017 Mar 23;60(6):2383-2400.

Herein we describe the design, synthesis, and evaluation of a novel series of oxadiazine-based gamma secretase modulators obtained via isosteric amide replacement and critical consideration of conformational restriction. Oxadiazine lead 47 possesses good in vitro potency with excellent predicted CNS drug-like properties and desirable ADME/PK profile. This lead compound demonstrated robust Abeta42 reductions and subsequent Abeta37 increases in both rodent brain and CSF at 30 mg/kg dosed orally.

gamma-Secretase Modulators (Amyloid-β production inhibitor) is a Amyloid-β production inhibitor. gamma-Secretase Modulators is useful for Alzheimer's disease.

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