Metabolism-Directed Design of Oxetane-Containing Arylsulfonamide Derivatives as γ-Secretase Inhibitors

Stepan, Antonia F.; Karki, Kapil; McDonald, W. Scott; Dorff, Peter H.; Dutra, Jason K.; DiRico, Kenneth J.; Won, Annie; Subramanyam, Chakrapani; Efremov, Ivan; O’Donnell, Christopher J; Nolan, Charles E.; Becker, Stacey L.; Pustilnik, Leslie; Sneed, Blossom; Sun, Hao; Lu, Yasong; Robshaw, Ashley; Riddell, David; O’Sullivan, Theresa J.; Sibley, E.; Capetta, Steven H.; Atchison, Kevin; Hallgren, Andrew J.; Miller, Emily; Wood, Anthony; Obach, R. Scott

doi:10.1021/jm200893p

Cited by 105 publications

(80 citation statements)

References 43 publications

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“…42 In this paper they showed that decreasing the ring size of the THP in their inhibitors improved the metabolic stability. Stability in HLM improved going from the THP (46) to THF (47) to the oxetane analogue (48).…”

Section: ■ Saturated Heterocyclesmentioning

confidence: 95%

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Mitigating Heterocycle Metabolism in Drug Discovery

2012

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In the past few decades, drug metabolism research has played an ever increasing role in the design of drugs. 1−3 In vitro metabolism assays 4 have become an integral part of the routine profiling of compounds made in drug discovery. 5 The data from these assays have allowed medicinal chemists to focus their efforts on compounds with improved metabolic stability. 6 Detailed metabolite identification studies are also done more routinely, which provide information on how to strategically replace or block metabolically labile sites. 7 Additionally, in vivo PK studies are regularly conducted in drug discovery, which helps to build in vitro−in vivo PK relationships. 4 The positive influence that these advances in PKDM sciences have had on drug discovery is reflected in the fact that fewer drug candidates fail in the clinic for PKDM related issues. 8 This suggests that medicinal chemists are successfully integrating the data generated by their PKDM colleagues into the design of compounds with fewer metabolic liabilities.Extensive data from metabolism studies have allowed medicinal chemists to develop general principles for reducing compound metabolism. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochemistry of their compounds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compounds. If the specific site of metabolism is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. 9 While several authors have reviewed these techniques for reducing metabolism, 5,10,11 there is no review that summarizes different approaches to improving the metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compounds.The majority of the examples that are included in this review came from searching the online open access database CHEMBL. 12 In addition to having pharmacology data on compounds from the medicinal chemistry literature, CHEMBL has over 120 000 points of data on the ADMET properties of compounds. With the help of the visualization software Spotfire, we were able to cull examples from the CHEMBL ADMET data that focused on heterocycles. We also identified examples from papers that cite leading reviews in the drug metabolism field 13−18 and were present in other recent reviews on drug metabolism. 19−22 The main criteria that we placed on the examples selected for this review was that the change made to improve metabolism had to occur at or near the heterocycle and nowhere else on the molecule. This allowed us to eliminate examples where a change made t...

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Section: ■ Saturated Heterocyclesmentioning

confidence: 95%

“…In vitro potency and metabolic stability of selected γ-secretase inhibitors. 42 The log D 7.4 was determined experimentally by Stepan et al using the method of Lombardo et al 43 Figure 15. In vitro potency and metabolic stability of selected CCR5 receptor antagonists.…”

Section: ■ Saturated Heterocyclesmentioning

confidence: 99%

Mitigating Heterocycle Metabolism in Drug Discovery

2012

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“…oxetanyl-containing compound EPZ015666 (N-[(2S)-2-hydroxy-3-(1,2,3,4-tetrahydroisoquinolin-2-yl)propyl]-6-[(oxetan-3-yl)amino]pyrimidine-4-carboxamide) and Stepan et al (2011) reported that members of an oxetanyl series of derivatives undergo oxidation of the cyclic ether moiety. In both studies, the P450-catalyzed oxidation took place on the carbon a to the oxygen atom, leading to unstable hemiacetal intermediates.…”

Section: Introductionmentioning

confidence: 99%

“…Considering the specific properties of the strained spiro oxetanylazetidinyl moiety in AZD1979 and the increasing interest in incorporating spirocycles as scaffolds in drug design (Wuitschik et al, 2008;Stepan et al, 2011;Carreira and Fessard, 2014;Zheng et al, 2014), it was of particular interest to characterize the metabolic pathways of this compound and the enzymology contributing to its clearance. In this study, we describe the non-P450-mediated formation of a metabolite M1 of AZD1979 and its structural characterization.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

Hayes

Grönberg

et al. 2016

Drug Metabolism and Disposition

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Oxetane moieties are increasingly being used by the pharmaceutical industry as building blocks in drug candidates because of their pronounced ability to improve physicochemical parameters and metabolic stability of drug candidates. The enzymes that catalyze the biotransformation of the oxetane moiety are, however, not well studied. The in vitro metabolism of a spiro oxetane-containing compound AZD1979 [(3-(4-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone] was studied and one of its metabolites, M1, attracted our interest because its formation was NAD(P)H independent. The focus of this work was to elucidate the structure of M1 and to understand the mechanism(s) of its formation. We established that M1 was formed via hydration and ring opening of the oxetanyl moiety of AZD1979. Incubations of AZD1979 using various human liver subcellular fractions revealed that the hydration reaction leading to M1 occurred mainly in the microsomal fraction. The underlying mechanism as a hydration, rather than an oxidation reaction, was supported by the incorporation of 18 O from H 2 18O into M1. Enzyme kinetics were performed probing the formation of M1 in human liver microsomes. The formation of M1 was substantially inhibited by progabide, a microsomal epoxide hydrolase inhibitor, but not by trans-4-[4-(1-adamantylcarbamoylamino)cyclohexyloxy]-benzoic acid, a soluble epoxide hydrolase inhibitor. On the basis of these results, we propose that microsomal epoxide hydrolase catalyzes the formation of M1. The substrate specificity of microsomal epoxide hydrolase should therefore be expanded to include not only epoxides but also the oxetanyl ring system present in AZD1979.

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“…Since its introduction, it has been used successfully in a traditional chemistry space [22,[56][57][58][59][60] as well as in the bRo5 programs [38].…”

Section: Experimental Log D Determinationsmentioning

confidence: 99%

Leveraging chromatography based physicochemical properties for efficient drug design

Goetz

Shalaeva²

2018

ADMET DMPK

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<p class="ADMETabstracttext">Applications of chromatography derived lipophilicity, polarity, and 3D concepts such as conformational states, exposed polarity and intramolecular hydrogen bonds (IMHB), are discussed along with recently developed methods for incorporating these concepts into drug design strategies. In addition, the drug design process is described with examples and practices used at Pfizer, as well as experimental and computed parameters used for parallel optimization of properties leading to drug candidate nominations.</p>

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Metabolism-Directed Design of Oxetane-Containing Arylsulfonamide Derivatives as γ-Secretase Inhibitors

Cited by 105 publications

References 43 publications

Mitigating Heterocycle Metabolism in Drug Discovery

Mitigating Heterocycle Metabolism in Drug Discovery

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

Leveraging chromatography based physicochemical properties for efficient drug design

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