Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints

Winneroski, Leonard L.; Erickson, Jon A.; Green, Steven J.; López, José E.; Stout, Stephanie; Porter, Warren J.; Timm, David E.; Audia, James E.; Barberis, Mario; Beck, James P.; Boggs, Leonard N.; Borders, Anthony R.; Boyer, Robert D.; Brier, Richard A.; Hembre, Erik J.; Hendle, J.; García‐Losada, Pablo; Minguez, Jose M.; Mathes, Brian M.; May, Patrick C.; Monk, Scott A.; Rankovic, Zoran; Shi, Yuan; Watson, Brian M.; Yang, Zhihui; Mergott, Dustin J.

doi:10.1016/j.bmc.2019.115194

Cited by 14 publications

(12 citation statements)

References 24 publications

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“…Despite both companies backed away from BACE1, the research in this field is still ongoing [ 180 , 181 ]. Novel compounds have been synthesized and tested towards BACE1 activity, including selective or multi-target drugs, natural compounds, and their derivatives [ 182 - 186 ].…”

Section: Bace Inhibitorsmentioning

confidence: 99%

Is It the Twilight of BACE1 Inhibitors?

Hrabinová

Pejchal

Kučera

et al. 2020

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: β-secretase (BACE1) has been regarded as a prime target for the development of amyloid beta (Aβ) lowering drugs in the therapy of Alzheimer´s disease (AD). Although the enzyme was discovered in 1991 and helped to formulate the Aβ hypothesis as one of the very important features of AD etiopathogenesis, progress in AD treatment utilizing BACE1 inhibitors has remained limited. Moreover, in the last years, major pharmaceutical companies have discontinued clinical trials of five BACE1 inhibitors that had been strongly perceived as prospective. In our review, the Aβ hypothesis, the enzyme, its functions, and selected substrates are described. BACE1 inhibitors are classified into four generations. Those that underwent clinical trials displayed adverse effects, including weight loss, skin rashes, worsening of neuropsychiatric symptoms, etc. Some inhibitors could not establish a statistically significant risk-benefit ratio, or even scored worse than placebo. We still believe that drugs targeting BACE1 may still hide some potential, but a different approach to BACE1 inhibition or a shift of focus to modulation of its trafficking and/or post-translational modification should now be followed.

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Section: Bace Inhibitorsmentioning

confidence: 99%

Is It the Twilight of BACE1 Inhibitors?

Hrabinová

Pejchal

Kučera

et al. 2020

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“…We recently described a series of cyclopropyl BACE inhibitors that leveraged a cyclopropyl group as a conformational constraint. 11 Initial efforts in this series focused on molecules such as cis-fused THF-aminothiazine 3 (Table 1). While 3 demonstrated high microsomal stability across species, we struggled to increase potency in this series beyond the ∼1 μM range.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor

et al. 2021

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The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNSpenetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.

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“…This was combined with modification of the fused tetrahydrofuran ring, ultimately leading to the identification of 67d , which demonstrated enzyme inhibitory potency comparable to 67a . Subcutaneous administration of 67d to PDAPP transgenic mice, which overexpress human amyloid precursor protein incorporating a V717F mutation, was associated with a dose-related increase in plasma exposure and a statistically significant reduction in mouse cortex Aβ levels at doses of both 30 mg/kg (24%) and 100 mg/kg (40%) . This study provides a compelling example of the need to install additional structural modifications in order to compensate for the effects of bioisosteric modification where topographical geometries are significantly altered.…”

Section: Bioisosteric Replacement Of Meta-substituted Phenyl Ringsmentioning

confidence: 99%

“…Replacement of the fluorophenyl group of the clinically evaluated BACE-1 inhibitor LY2886721 (67a) with a trans-substituted cyclopropyl ring was explored based on the premise of increasing sp 3 content as an approach to reduce both molecular weight and lipophilicity, a molecular edit also viewed as having the potential to alter the metabolic stability profile (Table 57). 140 In addition, the cyclopropyl moiety was viewed as an opportunity to probe vectors not available to the more planar 67a that would allow substituents to be projected into the S3 subpocket of the BACE-1 enzyme with alternate geometries. However, the simplest iteration of the design concept examined in the context of 67b and its reverse amide homologue 67c produced poorly active compounds, a result rationalized by an analysis of the X-ray cocrystal structure of 67b bound to the BACE-1 enzyme.…”

Section: Bioisosteric Replacement Ofmentioning

confidence: 99%

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

2021

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The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity in drug design either as a pharmacophore or as a scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at the beginning of the 21st century highlighted the indiscriminate deployment of phenyl rings as an important contributor to the poor physicochemical properties of advanced molecules, which limited their prospects of being developed into effective drugs. This Perspective deliberates on the design and applications of bioisosteric replacements for a phenyl ring that have provided practical solutions to a range of developability problems frequently encountered in lead optimization campaigns. While the effect of phenyl ring replacements on compound properties is contextual in nature, bioisosteric substitution can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG channel.

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Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints

Cited by 14 publications

References 24 publications

Is It the Twilight of BACE1 Inhibitors?

Is It the Twilight of BACE1 Inhibitors?

Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

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