Minimization of drug–drug interaction risk and candidate selection in a natural product-based class of gamma-secretase modulators

Hubbs, Jed L.; Fuller, Nathan O.; Austin, W. F.; Shen, Ruichao; Ma, Jing; Gong, Zongqiang; Li, Jian; McKee, Timothy D.; Loureiro, Robyn; Tate, Barbara; Dumin, Jo Ann; Ives, Jeffrey L.; Bronk, Brian S.

doi:10.1016/j.bmcl.2015.01.051

Cited by 9 publications

(7 citation statements)

References 10 publications

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“…While b-azetidinones are commonly observed in classical antibiotic therapies, intact azetidines have received limited attention but offered promising avenues in discovery of small molecules. Hubbs et al (2015) has demonstrated that substitution of a morpholine with azetidine disrupted the interactions of morpholine with heme porphyrin ring system, and was successfully applied as a strategy to reduce CYP450 inhibition of the unsubstituted morpholine. Packiarajan et al (2012) have reported a series of azetidinyl oxadiazoles as novel mGluR5 positive allosteric modulators (PAMs) where the azetidine carboxamides due to their low molecular weight (5350) and optimal cLog P (53) showed improved physicochemical and pharmacokinetic properties in comparison to Naryl pyrrolidinonyl oxadiazole leads.…”

Section: Discussionmentioning

confidence: 99%

Strategies toward optimization of the metabolism of a series of serotonin-4 partial agonists: investigation of azetidines as piperidine isosteres

Obach¹,

LaChapelle²,

Brodney

et al. 2016

Xenobiotica

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1.The first generation 5HT-4 partial agonist, 4-{4-[4-Tetrahydrofuran-3-yloxy)-benzo[d]isoxazol-3-yloxymethyl]-piperidin-1-ylmethyl}-tetrahydropyran-4-ol, PF-4995274 (TBPT), was metabolized to N-dealkylated (M1) and an unusual, cyclized oxazolidine (M2) metabolites. M1 and M2 demonstrated pharmacological activity at 5HT receptor subtypes warranting further investigation into their dispositional properties in humans; M2 was a minor component in vitro but was the pre-dominant metabolite identified in human plasma. 2.To shift metabolism away from the piperidine ring of TBPT, a series of heterocyclic replacements were designed, synthesized, and profiled. Groups including azetidines, pyrrolidines, as well as functionalized piperidines were evaluated with the goal of identifying an alternative group that maintained the desired potency, functional activity, and reduced turnover in human hepatocytes. 3.Activities of 4-substituted piperidines or pyrrolidine analogs at the pharmacological target were not significantly altered, but the same metabolic pathways of N-dealkylation and oxazolidine formation were still observed. Altering these to bridged ring systems lowered oxazolidine metabolite formation, but not N-dealkylation. 4.The effort concluded with identification of azetidines as second-generation 5HT partial agonists. These were neither metabolized via N-dealkylation nor converted to cyclized oxazolidine metabolites rather oxidized on the isoxazole ring. The use of azetidine as a replacement for aliphatic aza-heterocyclic rings in drug design to alter drug metabolism and pharmacology is discussed.

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Section: Discussionmentioning

confidence: 99%

Strategies toward optimization of the metabolism of a series of serotonin-4 partial agonists: investigation of azetidines as piperidine isosteres

Obach¹,

LaChapelle²,

Brodney

et al. 2016

Xenobiotica

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“…Optimization of the initial lead ultimately afforded the preclinical candidate SPI-1865 (Ab42 IC 50 of 106 nM) (Hubbs et al 2012(Hubbs et al , 2015Loureiro et al 2013). Following single oral doses of 10, 30, and 100 mg/kg in rat, SPI-1865 achieved brain Ab42 reduction of 21, 37, and 50%, respectively, at the 24-h time point following the final dose.…”

Section: Non-nsaid Heterocyclic Gsmsmentioning

confidence: 99%

Structural and Chemical Biology of Presenilin Complexes

Johnson

Pettersson

et al. 2017

Cold Spring Harb Perspect Med

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The presenilin proteins are the catalytic subunits of a tetrameric complex containing presenilin 1 or 2, anterior pharynx defective 1 (APH1), nicastrin, and PEN-2. Other components such as TMP21 may exist in a subset of specialized complexes. The presenilin complex is the founding member of a unique class of aspartyl proteases that catalyze the γ, ɛ, ζ site cleavage of the transmembrane domains of Type I membrane proteins including amyloid precursor protein (APP) and Notch. Here, we detail the structural and chemical biology of this unusual enzyme. Taken together, these studies suggest that the complex exists in several conformations, and subtle long-range (allosteric) shifts in the conformation of the complex underpin substrate access to the catalytic site and the mechanism of action for allosteric inhibitors and modulators. Understanding the mechanics of these shifts will facilitate the design of γ-secretase modulator (GSM) compounds that modulate the relative efficiency of γ, ɛ, ζ site cleavage and/or substrate specificity.

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“…While these GSMs demonstrated potent activity in vitro and in rodents [25,26] and had promising pharmacokinetic profiles in rodents, they also potently inhibited cytochrome P450 enzymes including CYP3A4. This property indicated a high potential to cause drug-drug interactions (DDIs) and therefore precluded consideration of these compounds as clinical development candidates [27]. Further optimization was required to minimize this potential for DDIs.…”

Section: Novel Gamma Secretase Modulators Based On Black Cohoshmentioning

confidence: 99%

“…Screening of N -modified 24- O -ethyl-3- O -morpholine series compounds for CYP inhibition revealed an inverse relationship between the combination of size and basicity of a substituent on the morpholine nitrogen and CYP inhibition (e.g., 20 > 21 > 22 at inhibiting CYP3A4) [27]. But, this was not a simple trend and computational modeling based on available structural data was used to develop a more detailed understanding of the available SAR with respect to CYP inhibition.…”

Section: Novel Gamma Secretase Modulators Based On Black Cohoshmentioning

confidence: 99%

“…This modeling effort suggested the synthesis of additional morpholine diamines. Among the compounds prepared to explore this molecular space, compounds 23 , 24 , and 25 (SPI-1865; Aβ42 IC 50 = 75~110 nM) were chosen for further characterization based on maintaining potency, having lower levels of CYP inhibition, and a certain level of structural diversity (Figure 8) [27,28]. Pharmacokinetic studies in rats for these compounds showed low clearance, high volumes of distribution, a long half-life (79–129 h) and moderate to good bioavailability.…”

Section: Novel Gamma Secretase Modulators Based On Black Cohoshmentioning

confidence: 99%

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Natural Product and Natural Product-Derived Gamma Secretase Modulators from Actaea Racemosa Extracts

Findeis¹,

Schroeder

Creaser³

et al. 2015

Medicines

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Alzheimer’s disease is characterized by pathogenic oligomerization, aggregation, and deposition of amyloid beta peptide (Aβ), resulting in severe neuronal toxicity and associated cognitive dysfunction. In particular, increases in the absolute or relative level of the major long form of Aβ, Aβ42, are associated with increased cellular toxicity and rapidity of disease progression. As a result of this observation, screening to identify potential drugs to reduce the level of Aβ42 have been undertaken by way of modulating the proteolytic activity of the gamma secretase complex without compromising its action on other essential substrates such as Notch. In this review we summarize results from a program that sought to develop such gamma secretase modulators based on novel natural products identified in the extract of Actaea racemosa, the well-known botanical black cohosh. Following isolation of compound 1 (SPI-014), an extensive medicinal chemistry effort was undertaken to define the SAR of 1 and related semisynthetic compounds. Major metabolic and physicochemical liabilities in 1 were overcome including replacement of both the sugar and acetate moieties with more stable alternatives that improved drug-like properties and resulted in development candidate 25 (SPI-1865). Unanticipated off-target adrenal toxicity, however, precluded advancement of this series of compounds into clinical development.

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Minimization of drug–drug interaction risk and candidate selection in a natural product-based class of gamma-secretase modulators

Cited by 9 publications

References 10 publications

Strategies toward optimization of the metabolism of a series of serotonin-4 partial agonists: investigation of azetidines as piperidine isosteres

Strategies toward optimization of the metabolism of a series of serotonin-4 partial agonists: investigation of azetidines as piperidine isosteres

Structural and Chemical Biology of Presenilin Complexes

Natural Product and Natural Product-Derived Gamma Secretase Modulators from Actaea Racemosa Extracts

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