Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor

Cumming, Jared N.; Smith, Elizabeth M.; Wang, Lingyan; Misiaszek, Jeffrey; Durkin, James; Pan, Jianping; Iserloh, Ulrich; Wu, Yusheng; Zhu, Zhiwei; Strickland, Corey; Voigt, Johannes H.; Chen, Xia; Kennedy, Matthew; Kuvelkar, Reshma; Hyde, Lynn A.; Cox, Kathleen; Favreau, Leonard; Czarniecki, Michael; Greenlee, William J.; McKittrick, Brian A.; Parker, Eric M.; Stamford, Andrew W.

doi:10.1016/j.bmcl.2012.02.013

Cited by 129 publications

(136 citation statements)

References 28 publications

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“…These efforts relied heavily on BACE1 X‐ray crystallography and computational modeling to aid rational chemical design decisions that achieved high affinity binding coupled with robust oral pharmacokinetic and CSF Aβ lowering efficacy in rodents as exemplified by Merck F (Cumming et al . ). Subsequent medicinal chemistry efforts pursued ring expansion of the iminohydantoin warhead to generate the novel 6‐membered C5‐substituted iminopyrimidinone core, Merck J in Fig.…”

Section: Bace Inhibition – Therapeutic Potential Of Small Molecules Amentioning

confidence: 97%

Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects

Vassar

Kuhn

Haass

et al. 2014

Journal of Neurochemistry

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The β-site APP cleaving enzymes 1 and 2 (BACE1 and BACE2) were initially identified as transmembrane aspartyl proteases cleaving the amyloid precursor protein (APP). BACE1 is a major drug target for Alzheimer’s disease because BACE1-mediated cleavage of APP is the first step in the generation of the pathogenic amyloid-β peptides. BACE1, which is highly expressed in the nervous system, is also required for myelination by cleaving neuregulin 1. Several recent proteomic and in vivo studies usingBACE1-andBACE2-deficient mice demonstrate a much wider range of physiological substrates and functions for both proteases within and outside of the nervous system. For BACE1 this includes axon guidance, neurogenesis, muscle spindle formation, and neuronal network functions, whereas BACE2 was shown to be involved in pigmentation and pancreatic β-cell function. This review highlights the recent progress in understanding cell biology, substrates, and functions of BACE proteases and discusses the therapeutic options and potential mechanism-based liabilities, in particular for BACE inhibitors in Alzheimer’s disease.

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Section: Bace Inhibition – Therapeutic Potential Of Small Molecules Amentioning

confidence: 97%

Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects

Vassar

Kuhn

Haass

et al. 2014

Journal of Neurochemistry

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276

270

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“…First, the propynyl group of 16 binds deep in the S3 sub-pocket where it is positioned to engage in a hydrophobic interaction with Ala 335 as previously reported for 2 . 18 Second, in comparison to the cocrystal structure of 4 , the flap is in a more closed conformation, forming a pocket which accommodates the chloro substituent while positioning the side-chain of flap Tyr 71 in close proximity to the methylene of the iminopyrimidinone core.…”

mentioning

confidence: 99%

Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS Aβ Reduction

Stamford¹,

Scott²,

Li³

et al. 2012

ACS Med. Chem. Lett.

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Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach to the treatment of Alzheimer’s disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aβ levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aβ40 levels when administered orally to rats.

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“…Reduction of Ab formation through b-secretase inhibition is considered to be a promising approach to halt or to slow the progression of the disease. The effectiveness of orally administered b-secretase inhibitors in decreasing Ab levels in the CNS has been demonstrated in mice (May et al, 2011;Lu et al, 2012a;Swahn et al, 2012a), rats (Cumming et al, 2012;Weiss et al, 2012;Wood et al, 2012), guinea pigs (Truong et al, 2010;Gravenfors et al, 2012), dogs (May et al, 2011), monkeys (Sankaranarayanan et al, 2009;Lu et al, 2012b), and humans (May et al, 2011;Forman et al, 2012;Lai et al, 2012). It remains to be proven, however, whether b-secretase inhibition ultimately leads to improvement of a clinically meaningful end point, such as attenuated cognitive decline in patients with Alzheimer's disease.…”

Section: Introductionmentioning

confidence: 99%

Biotransformation of Two β-Secretase Inhibitors Including Ring Opening and Contraction of a Pyrimidine Ring

et al. 2013

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Recently, the discovery of the aminoisoindoles as potent and selective inhibitors of b-secretase was reported, including the close structural analogs compound (S)-1-pyridin-4-yl-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine [(S)-25] and (S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate (AZD3839), the latter being recently progressed to the clinic. The biotransformation of (S)-25 was investigated in vitro and in vivo in rat, rabbit, and human and compared with AZD3839 to further understand the metabolic fate of these compounds. In vitro, CYP3A4 was the major responsible enzyme and metabolized both compounds to a large extent in the commonly shared pyridine and pyrimidine rings. The main proposed metabolic pathways in various in vitro systems were N-oxidation of the pyridine and/or pyrimidine ring and conversion to 4-pyrimidone and pyrimidine-2, 4-dione. Both compounds were extensively metabolized, and more than 90% was excreted in feces after intravenous administration of radiolabeled compound to the rat. Here, the main pathways were N-oxidation of the pyridine and/or pyrimidine ring and a ring contraction of the pyrimidine ring into an imidazole ring. Ringcontracted metabolites accounted for 25% of the total metabolism in the rat for (S)-25, whereas the contribution was much smaller for AZD3839. This metabolic pathway was not foreseen on the basis of the obtained in vitro data. In conclusion, we discovered an unusual metabolic pathway of aryl-pyrimidine-containing compounds by a ring-opening reaction followed by elimination of a carbon atom and a ring closure to form an imidazole ring.

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Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor

Cited by 129 publications

References 28 publications

Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects

Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects

Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS Aβ Reduction

Biotransformation of Two β-Secretase Inhibitors Including Ring Opening and Contraction of a Pyrimidine Ring

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