Design, synthesis, and structure–activity relationship of novel orally efficacious pyrazole/sulfonamide based dihydroquinoline γ-secretase inhibitors

Truong, Anh P.; Aubele, Danielle L.; Probst, Gary D.; Neitzel, Martin L.; Semko, Chris M.; Bowers, Simeon; Dressen, Darren; Hom, Roy K.; Konradi, Andrei W.; Sham, Hing L.; Garofalo, Albert W.; Keim, Pamela S.; Wu, Jing; Dappen, Michael S.; Wong, Karina; Goldbach, Erich; Quinn, Kevin P.; Sauer, John‐Michael; Brigham, Elizabeth F.; Wallace, William H.; Nguyen, Lan K.; Hemphill, Susanna S.; Bova, Michael P.; Basi, Guriqbal S.

doi:10.1016/j.bmcl.2009.07.092

Cited by 36 publications

(7 citation statements)

References 16 publications

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“…The microsomal stability was measured for all of these inhibitors, which generally exhibited poor to moderate oxidative stability across species (mouse, rat, and human). [24] Because the inhibitors 1 a-7 all showed low lipophilicity (clog P < 3), it was surmised that this liability might be due to site-specific oxidation. In the case of the heteroaryl-substituted analogues, this likely meant oxidation at the carbon atom adjacent to a heteroatom within the pendant aromatic ring.…”

Section: Resultsmentioning

confidence: 99%

Selective and Brain‐Permeable Polo‐like Kinase‐2 (Plk‐2) Inhibitors That Reduce α‐Synuclein Phosphorylation in Rat Brain

et al. 2013

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Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition in vivo. One such compound significantly decreased phosphorylation of α-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease.

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Section: Resultsmentioning

confidence: 99%

Selective and Brain‐Permeable Polo‐like Kinase‐2 (Plk‐2) Inhibitors That Reduce α‐Synuclein Phosphorylation in Rat Brain

et al. 2013

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“…Preventing the oxidation of aliphatic carbons can be extremely challenging, however, mitigating the oxidation of aryl rings can be more facile. Thus, the quinoline series 1 ostensibly offered the lowest hurdle to prepare metabolically stable inhibitors. This series had a single aliphatic carbon (the site of oxidation), whereas both the piperidine 2 and bicyclic 3 series bore multiple aliphatic carbons as potential sites for oxidation (see refs and for early development of the series).…”

Section: Results Discussion and Chemistrymentioning

confidence: 99%

Discovery of (R)-4-Cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-Cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): Metabolically Stable γ-Secretase Inhibitors that Selectively Inhibit the Production of Amyloid-β over Notch

Probst¹,

Aubele²,

Bowers³

et al. 2013

J. Med. Chem.

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Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aβ in the CSF of healthy human volunteers.

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“…In summary, the in vivo selectivity of ELN475516 from a mouse seven-day safety model corroborates the improved selectivity estimated for this compound in the cellular SNC assay, confirming APP selective inhibition of gamma-secretase in vivo by this novel pyrazolylazabicyclo(3.3.1)nonane sulfonamide. ELN475156 represents a validated foundation for further lead optimization to discover APP selective second generation GSIs with improved safety and drug like properties suitable for chronic AD therapy [60,98,103,104]. …”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

et al. 2010

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IntroductionInhibition of gamma-secretase presents a direct target for lowering Aβ production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy.MethodsIn vitro assays monitoring inhibitor potencies at APP γ-site cleavage (equivalent to Aβ40), and Notch ε-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of Aβ production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain Aβ was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain Aβ reduction vs. Notch signaling endpoints in periphery.ResultsThe APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting Aβ production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain Aβ in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain Aβ was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested.ConclusionsThe discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.

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Design, synthesis, and structure–activity relationship of novel orally efficacious pyrazole/sulfonamide based dihydroquinoline γ-secretase inhibitors

Cited by 36 publications

References 16 publications

Selective and Brain‐Permeable Polo‐like Kinase‐2 (Plk‐2) Inhibitors That Reduce α‐Synuclein Phosphorylation in Rat Brain

Selective and Brain‐Permeable Polo‐like Kinase‐2 (Plk‐2) Inhibitors That Reduce α‐Synuclein Phosphorylation in Rat Brain

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

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