Cyclic Hydroxyamidines as Amide Isosteres: Discovery of Oxadiazolines and Oxadiazines as Potent and Highly Efficacious γ-Secretase Modulators in Vivo

Sun, Zhongyue; Asberom, Theodros; Bara, Thomas; Bennett, Chad; Burnett, Duane A.; Chu, Inhou; Clader, John W.; Cohen-Williams, Mary; Cole, David; Czarniecki, Michael; Durkin, James; Gallo, Gioconda; Greenlee, William J.; Josien, Hubert; Huang, Xianhai; Hyde, Lynn A.; Jones, Nicholas A.; Kazakevich, Irina; Li, Hongmei; Liu, Xiaoxiang; Lee, Julie; MacCoss, Malcolm; Mandal, Mihir; McCracken, Troy M.; Nomeir, Amin A.; Mazzola, Robert; Palani, Anandan; Parker, Eric M.; Pissarnitski, Dmitri; Qin, Jun; Song, Lixin; Terracina, Giuseppe; Vicarel, Monica; Voigt, Johannes H.; Xu, Ruo; Zhang, Lili; Zhang, Qi; Zhao, Zhiqiang; Zhu, Xiaohong; Zhu, Zhiwei

doi:10.1021/jm201407j

Cited by 49 publications

(31 citation statements)

References 52 publications

(48 reference statements)

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“…94 A conformational constraint was engineered between the amide carbonyl and the α-methyl carbon via a cyclized hydroxy amidine (oxadiazoline) which maintains the potential hydrogen bond acceptor of the amide. Rewardingly, compound 3 had good potency in cells (EC 50 = 58 nM).…”

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confidence: 99%

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 A ring expansion of the oxadiazolines by the Schering group led to the discovery of the oxadiazine scaffold. 94,95 A trifluorophenyl was substituted onto either the C3 or C4 position of the fused oxadiazine to afford potent compounds with unfortunately high cLogPs (4.6) and low MPO scores (3.4). Substitution at the C3 position afforded compound 5 which demonstrated good in vitro potency (EC 50 = 48 nM).…”

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confidence: 99%

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Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?

Bursavich¹,

Harrison²,

Blain³

2016

J. Med. Chem.

125

123

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The rapidly aging population desperately requires new therapies for Alzheimer's disease. Despite years of pharmaceutical research, limited clinical success has been realized, with several failed disease modification therapies in recent years. On the basis of compelling genetic evidence, the pharmaceutical industry has put a large emphasis on brain beta amyloid (Aβ) either through its removal via antibodies or by targeting the proteases responsible for its production. In this Perspective, we focus on the development of small molecules that improve the activity of one such protease, gamma secretase, through an allosteric binding site to preferentially increase the concentration of the shorter non-amyloidogenic Aβ species. After a few early failures due to poor drug-like properties, the industry is now on the cusp of delivering gamma secretase modulators for clinical proof-of-mechanism studies that combine potency and efficacy with improved drug-like properties such as lower cLogP, high central nervous system multiparameter optimization scores, and high sp(3) character.

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confidence: 99%

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confidence: 99%

Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?

Bursavich¹,

Harrison²,

Blain³

2016

J. Med. Chem.

125

123

View full text Add to dashboard Cite

show abstract

“…Structural modifications have been extensively performed on several classes of compounds. For example, analogs of the arylimidazole containing the olefin linker scaffold have been developed, namely oxadiazine (compounds 79 and 80 ) and oxadiazepine (compound 81 ) . Further studies substituted the olefin linker with a nitrogen linker as shown in aniline‐based compounds containing benzimidazole (compound 82 ), indazole (compound 83 ), benzoxazole (compound 84 ), pyrimidine fused with five‐ or six‐membered rings (compounds 85 ‐ 87 ) and pyrimidomorpholine (compounds 88 ‐ 90 ).…”

Section: γ‐Secretase Inhibitorsmentioning

confidence: 99%

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Schaduangrat

Prachayasittikul

Choomwattana

et al. 2019

Medicinal Research Reviews

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The continual increase of the aging population worldwide renders Alzheimer's disease (AD) a global prime concern. Several attempts have been focused on understanding the intricate complexity of the disease's development along with the on‐ andgoing search for novel therapeutic strategies. Incapability of existing AD drugs to effectively modulate the pathogenesis or to delay the progression of the disease leads to a shift in the paradigm of AD drug discovery. Efforts aimed at identifying AD drugs have mostly focused on the development of disease‐modifying agents in which effects are believed to be long lasting. Of particular note, the secretase enzymes, a group of proteases responsible for the metabolism of the β‐amyloid precursor protein (βAPP) and β‐amyloid (Aβ) peptides production, have been underlined for their promising therapeutic potential. This review article attempts to comprehensively cover aspects related to the identification and use of drugs targeting the secretase enzymes. Particularly, the roles of secretases in the pathogenesis of AD and their therapeutic modulation are provided herein. Moreover, an overview of the drug development process and the contribution of computational (in silico) approaches for facilitating successful drug discovery are also highlighted along with examples of relevant computational works. Promising chemical scaffolds, inhibitors, and modulators against each class of secretases are also summarized herein. Additionally, multitarget secretase modulators are also taken into consideration in light of the current growing interest in the polypharmacology of complex diseases. Finally, challenging issues and future outlook relevant to the discovery of drugs targeting secretases are also discussed.

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“…Clinical trials involving 33 revealed that it decreases plasma Aβ levels in humans and lends support to the development of more improved compounds. One improvement was the insertion of an oxadiazoline ring that resulted on compound 34 (Figure ) with Aβ 42 EC 50 =29 n m , which is able to decrease the amount of Aβ 42 by 66 %; however, it shows poor CNS druglike properties . Another interesting study resulted in compound 36 (Figure ), which presents high potency (EC 50 =16 n m ), decreased Aβ 42 by 62 %, and has improved druglike properties; however, it shows indications of liver toxicity .…”

Section: γ‐Secretasementioning

confidence: 99%

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

et al. 2019

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Among neurodegenerative disorders, Alzheimer's disease (AD) is the most common type of dementia, and there is an urgent need to discover new and efficacious forms of treatment for it. Pathological patterns of AD include cholinergic dysfunction, increased β‐amyloid (Aβ) peptide concentration, the appearance of neurofibrillary tangles, among others, all of which are strongly associated with specific biological targets. Interactions observed between these targets and potential drug candidates in AD most often occur by competitive mechanisms driven by orthosteric ligands that sometimes result in the production of side effects. In this context, the allosteric mechanism represents a key strategy; this can be regarded as the selective modulation of such targets by allosteric modulators in an advantageous manner, as this may decrease the likelihood of side effects. The purpose of this review is to present an overview of compounds that act as allosteric modulators of the main biological targets related to AD.

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Cyclic Hydroxyamidines as Amide Isosteres: Discovery of Oxadiazolines and Oxadiazines as Potent and Highly Efficacious γ-Secretase Modulators in Vivo

Cited by 49 publications

References 52 publications

Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?

Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

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