Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and Efficacious γ-Secretase Inhibitors

Ye, Xiaocong M.; Konradi, Andrei W.; Smith, Jenifer; Xu, Yinchuan; Dressen, Darren; Garofalo, Albert W.; Marugg, Jennifer L.; Sham, Hing L.; Truong, Anh P.; Jagodziński, Jacek; Pleiss, Michael A.; Zhang, Hongbin; Goldbach, Erich; Sauer, John‐Michael; Brigham, Elizabeth F.; Bova, Michael P.; Basi, Guriqbal S.

doi:10.1016/j.bmcl.2010.02.039

Cited by 16 publications

(8 citation statements)

References 13 publications

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“…Interestingly, despite equipotent inhibition of APP and Notch processing by gamma-secretase, sulfones are reported to be well tolerated at 3 mg/kg dose in a three- month treatment study in the Tg2576 mouse model [14], although higher doses were not reported. In a similar vein, whereas potent piperdine containing sulfonamide GSI have also been described [90,94-97], APP selectivity has only been reported following incorporation of a pyrazole substituent into the piperdine sulfonamide core [98]. …”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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“…11 , compound 2 ) recently completed phase I [128-130]. Another NOTCH-sparing GSI from Elan, ELND-006, has entered Phase I (structure undisclosed, for further reading see reference [131] and compound 3 in Fig. 11 ).…”

Section: Chemical Development and Clinical Perspective Of γ-Secretasementioning

confidence: 99%

Chemical Biology, Molecular Mechanism and Clinical Perspective of γ - Secretase Modulators in Alzheimers Disease

Bulic¹,

Neß²,

Hahn³

et al. 2011

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Comprehensive evidence supports that oligomerization and accumulation of amyloidogenic Aβ42 peptides in brain is crucial in the pathogenesis of both familial and sporadic forms of Alzheimer's disease. Imaging studies indicate that the buildup of Aβ begins many years before the onset of clinical symptoms, and that subsequent neurodegeneration and cognitive decline may proceed independently of Aβ. This implies the necessity for early intervention in cognitively normal individuals with therapeutic strategies that prioritize safety. The aspartyl protease γ-secretase catalyses the last step in the cellular generation of Aβ42 peptides, and is a principal target for anti-amyloidogenic intervention strategies. Due to the essential role of γ-secretase in the NOTCH signaling pathway, overt mechanism-based toxicity has been observed with the first generation of γ-secretase inhibitors, and safety of this approach has been questioned. However, two new classes of small molecules, γ-secretase modulators (GSMs) and NOTCH-sparing γ-secretase inhibitors, have revitalized γ-secretase as a drug target in AD. GSMs are small molecules that cause a product shift from Aβ42 towards shorter and less toxic Ab peptides. Importantly, GSMs spare other physiologically important substrates of the γ-secretase complex like NOTCH. Recently, GSMs with nanomolar potency and favorable in vivo properties have been described. In this review, we summarize the knowledge about the unusual proteolytic activity of γ-secretase, and the chemical biology, molecular mechanisms and clinical perspective of compounds that target the γ-secretase complex, with a particular focus on GSMs.

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“…3- 5,6,pyridines were first synthesized as a new class of antihypertensive agent (Winters et al, 1985) and compounds of this type have subsequently been used for the treatment of neuropathic pain (Yogeeswari et al, 2013). 5- 5,6,pyridines have been shown (Ye et al, 2010) to act as potent inhibitors of -secretase, an intramembrane protease. Structural studies of tetrahydropyrazolo [4,3-c]pyridines are rather few in number (Smith et al, 2007;Ye et al, 2010;Guo, 2011;Petersen et al, 2013), although the structure of a hexahydro derivative has been reported (Shahani et al, 2010) and, prompted by this comparative paucity of structural data, we now report the molecular and supramolecular structures of three closely related compounds of this class, namely 1-(4fluorophenyl)-5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, (I), 1-(4-chlorophenyl)-5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-4,5,6,7- -1H-pyrazolo[4,3-c]pyridine, (II), and 1-(3-methylphenyl)-5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-4,5,6,7tetrahydro-1H-pyrazolo [4,3-c]pyridine, (III) (see Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Three closely related 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridines: synthesis, molecular conformations and hydrogen bonding in zero, one and two dimensions

et al. 2017

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In each of 1-(4-fluorophenyl)-5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, CHFNOS, (I), 1-(4-chlorophenyl)-5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, CHClFNOS, (II), and 1-(3-methylphenyl)-5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, CHFNOS, (III), the reduced pyridine ring adopts a half-chair conformation with the methylsulfonyl substituent occupying an equatorial site. Although compounds (I) and (II) are not isostructural, having the space groups Pbca and P222, respectively, their molecular conformations are very similar, but the conformation of compound (III) differs from those of (I) and (II) in the relative orientation of the N-benzyl and methylsulfonyl substituents. In compounds (II) and (III), but not in (I), the trifluoromethyl groups are disordered over two sets of atomic sites. Molecules of (I) are linked into centrosymmetric dimers by C-H...π(arene) hydrogen bonds, molecules of (II) are linked by two C-H...O hydrogen bonds to form ribbons of R(18) rings, which are themselves further linked by a C-Cl...π(arene) interaction, and a combination of C-H...O and C-H...π(arene) hydrogen bonds links the molecules of (III) into sheets. Comparisons are made with the structures of some related compounds.

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Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and Efficacious γ-Secretase Inhibitors

Cited by 16 publications

References 13 publications

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

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

Chemical Biology, Molecular Mechanism and Clinical Perspective of γ - Secretase Modulators in Alzheimers Disease

Three closely related 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridines: synthesis, molecular conformations and hydrogen bonding in zero, one and two dimensions

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