Pyridazine-derived γ-secretase modulators

Wan, Zhimin; Hall, Adrian; Jin, Yun; Xiang, Jia‐Ning; Yang, Eric; Eatherton, Andrew J.; Smith, Beverley; Yang, Guang; Yu, Haihua; Wang, Ju; Liang, Y. T.; Lau, Lit-Fui; Yang, Ting; Mitchell, William L.; Cai, Wei; Zhang, Xiaomin; Sang, Yingxia; Wang, Yonghui; Tong, Zhaolong; Cheng, Ziqiang; Hussain, Ishrut; Elliott, John D.; Matsuoka, Yasuji

doi:10.1016/j.bmcl.2011.04.143

Cited by 18 publications

(8 citation statements)

References 17 publications

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“…In general, the GSMs fall into three groupings: 1) NSAID-derived carboxylic acids, 2) non-NSAID heterocyclics, and 3) natural product–derived GSMs. Different GSMs produce different shifts in cleavage preference, with some showing increases in A β 38 and others showing increases in A β 37 peptide generation with concomitant reductions in A β 42 and A β 40 ( Caldwell et al, 2010 ; Kounnas et al, 2010 ; Wan et al, 2011a , b ; Borgegard et al, 2012 ; Tate et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

The -Secretase Modulator, BMS-932481, Modulates A Peptides in the Plasma and Cerebrospinal Fluid of Healthy Volunteers

Soares¹,

Gąsior

Toyn³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The pharmacokinetics, pharmacodynamics, safety, and tolerability of BMS-932481, a γ-secretase modulator (GSM), were tested in healthy young and elderly volunteers after single and multiple doses. BMS-932481 was orally absorbed, showed dose proportionality after a single dose administration, and had approximately 3-fold accumulation after multiple dosing. High-fat/caloric meals doubled the Cmax and area under the curve and prolonged Tmax by 1.5 hours. Consistent with the preclinical pharmacology of GSMs, BMS-932481 decreased cerebrospinal fluid (CSF) Aβ39, Aβ40, and Aβ42 while increasing Aβ37 and Aβ38, thereby providing evidence of γ-secretase enzyme modulation rather than inhibition. In plasma, reductions in Aβ40 and Aβ42 were observed with no change in total Aβ; in CSF, modest decreases in total Aβ were observed at higher dose levels. Increases in liver enzymes were observed at exposures associated with greater than 70% CSF Aβ42 lowering after multiple dosing. Although further development was halted due to an insufficient safety margin to test the hypothesis for efficacy of Aβ lowering in Alzheimer’s disease, this study demonstrates that γ-secretase modulation is achievable in healthy human volunteers and supports further efforts to discover well tolerated GSMs for testing in Alzheimer’s disease and other indications.

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Section: Introductionmentioning

confidence: 99%

The -Secretase Modulator, BMS-932481, Modulates A Peptides in the Plasma and Cerebrospinal Fluid of Healthy Volunteers

Soares¹,

Gąsior

Toyn³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…The first paper [35] detailed compounds such as (16) (Figure 3.5). The first paper [35] detailed compounds such as (16) (Figure 3.5).…”

Section: Gskmentioning

confidence: 99%

“…This gave a 22% decrease in brain Ab 42 and a 17% increase in brain Ab 38 levels. For comparison purposes, note the disparity between ChemDraw cLogP values for (34), (35) and (36) This compound was more active and decreased brain Ab 42 by 62% and gave a 66% increase in brain Ab 38 .…”

Section: Janssenmentioning

confidence: 99%

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γ-Secretase Modulators

Hall

Patel

2014

Progress in Medicinal Chemistry

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“…In general, the NSAIDs and their derivatives decrease A β 1-42 and increase A β 1-38, while having no effect on A β 1-40 production. Other GSMs, with chemical structures unrelated to the NSAIDs ( Caldwell et al, 2010 ; Kounnas et al, 2010 ; Wan et al, 2011a , b ; Borgegard et al, 2012 ; Tate et al, 2012 ; Yu et al, 2014 ), decrease A β 1-40 in addition to A β 1-42, while simultaneously increasing one or more of the shorter peptides A β 1-37, A β 1-38, or A β 1-39. The common element of all GSMs is that they decrease A β 1-42 without inhibition of overall A β 1-x production.…”

Section: Introductionmentioning

confidence: 99%

Robust Translation of -Secretase Modulator Pharmacology across Preclinical Species and Human Subjects

Toyn

Boy²,

Raybon³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The amyloid-β peptide (Aβ)—in particular, the 42–amino acid form, Aβ1-42—is thought to play a key role in the pathogenesis of Alzheimer’s disease (AD). Thus, several therapeutic modalities aiming to inhibit Aβ synthesis or increase the clearance of Aβ have entered clinical trials, including γ-secretase inhibitors, anti-Aβ antibodies, and amyloid-β precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aβ1-42 production, and may also decrease Aβ1-40 while simultaneously increasing one or more shorter Aβ peptides, such as Aβ1-38 and Aβ1-37. GSMs are particularly attractive because they do not alter the total amount of Aβ peptides produced by γ-secretase activity; they spare the processing of other γ-secretase substrates, such as Notch; and they do not cause accumulation of the potentially toxic processing intermediate, β-C-terminal fragment. This report describes the translation of pharmacological activity across species for two novel GSMs, (S)-7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (BMS-932481) and (S,Z)-17-(4-chloro-2-fluorophenyl)-34-(3-methyl-1H-1,2,4-triazol-1-yl)-16,17-dihydro-15H-4-oxa-2,9-diaza-1(2,4)-cyclopenta[d]pyrimidina-3(1,3)-benzenacyclononaphan-6-ene (BMS-986133). These GSMs are highly potent in vitro, exhibit dose- and time-dependent activity in vivo, and have consistent levels of pharmacological effect across rats, dogs, monkeys, and human subjects. In rats, the two GSMs exhibit similar pharmacokinetics/pharmacodynamics between the brain and cerebrospinal fluid. In all species, GSM treatment decreased Aβ1-42 and Aβ1-40 levels while increasing Aβ1-38 and Aβ1-37 by a corresponding amount. Thus, the GSM mechanism and central activity translate across preclinical species and humans, thereby validating this therapeutic modality for potential utility in AD.

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Pyridazine-derived γ-secretase modulators

Cited by 18 publications

References 17 publications

The -Secretase Modulator, BMS-932481, Modulates A Peptides in the Plasma and Cerebrospinal Fluid of Healthy Volunteers

The -Secretase Modulator, BMS-932481, Modulates A Peptides in the Plasma and Cerebrospinal Fluid of Healthy Volunteers

γ-Secretase Modulators

Robust Translation of -Secretase Modulator Pharmacology across Preclinical Species and Human Subjects

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