Poor Physiochemical Properties Research Articles

Wet refining: A novel approach for modification of wheat bran fiber

To address the poor physiochemical and functional properties a novel wet refining (using Valley Beater) treatment was adopted for modification of wheat bran fiber. Valley Beater, which is valuable equipment in the pulp and paper industry to improve fiber properties, was optimized for wheat bran using response surface methodology. The obtained modified bran fiber was further compared, separately and in combination with the moist heat modified wheat bran. The effect of modifications was accessed in terms of physiochemical, functional, morphological, structural, and antioxidant properties. Particle size, SEM, FT-IR spectroscopy, and XRD analysis depicted the successful modification effects with a good explanation of different improved properties. The wet refining process significantly improved the bran fiber water absorption, oil absorption, water swelling, and sedimentation properties along with increasing the fines content. Although, the moist heat modification showed a positive effect on soluble dietary fiber, and glucose absorption capacity. Still, the wet refining modification was found to ameliorate bran fiber antioxidant properties such as total phenolic content, DPPH scavenging capacity, and total reducing power. Categorically, the combined (wet refining followed by moist heating) modification process was most suitable with more desirable effects. Our research manifested that the wet refining process in combination with moist heat treatment can be used to improve nutritional and product-making characteristics of wheat bran fiber and thus can be adopted for preparing high-fiber food products.

Pharmacokinetic evaluation of poorly soluble compounds formulated as nano- or microcrystals after intraperitoneal injection to mice

Intraperitonial (i.p.) delivery during initial stages of drug discovery can allow efficacy readouts for compounds which have suboptimal pharmacokinetics (PK) due to poor physiochemical properties and/or oral bioavailability. A major limitation for widespread use of i.p. administration is the paucity of published data and unclear mechanisms of absorption, particularly when using complex formulations. The aim of the present study was to investigate the PK of poorly soluble compounds with low oral bioavailability when administered i.p. as crystalline nano- and microsuspensions. Three compounds, with varying aqueous solubility (2, 7, and 38 µM, at 37 °C), were dosed to mice at 10 and 50 mg/kg. In vitro dissolution confirmed that nanocrystals dissolved faster than microcrystals and hence were expected to result in higher exposure after i.p. dosing. Surprisingly, the increase in dissolution rate with decrease in particle size did not result in higher in vivo exposure. In contrast, the microcrystals showed higher exposure. The potential of smaller particles to promote access to the lymphatic system is hypothesized and discussed as one plausible explanation. The present work demonstrates the importance of understanding physicochemical properties of drug formulations in the context of the microphysiology at the delivery site and how that knowledge can be leveraged to alter systemic PK.

Vacuum fractional distillation of biocrude oil and the immobilization of harmful metal

• Fractional distillation can obviously decrease the O and S content in biocrude. • The majority of the alkali/heavy metals migrated to distillation residue. • Over 35.0% of the As in raw biocrude oil lead to distillation oil. • In-situ catalytic reaction of CaCO 3 /K 2 CO 3 promotes the denitrification process. The high heteroatom and excessive metals induce poor physiochemical properties of algae-biocrude, causing either damage to engine or air pollution. This study systematically investigated elements migration behaviors during vacuum fractional distillation of raw biocrude. Comparing with the raw biocrude, the oxygen (O) and sulfur (S) content in the distillates was greatly decreased by 47.6% and 44.3%, respectively. Over 96.0% of the Ca, K, and Pb in the raw biocrude concentrated into the distillation residue. Notably, the migration morphology of As is very special with only 63.1% of the As migrated into the residue associated with organic As in biocrude. In-situ catalytic reaction of CaCO 3 /K 2 CO 3 may promote the metal migration, denitrogenation, and desulfurization process. The distillate oil obtained at 275 °C (F6) has the highest abundant of saturated hydrocarbon (62.69%) with relatively high H/C and low N/C among all the distillates, which was probably an excellent transport alternative biofuel.

Special Focus Issue - Targeted protein degradation: a new paradigm in medicinal chemistry.

Special Focus Issue - Targeted protein degradation: a new paradigm in medicinal chemistry.

Synthesis of the 26-Membered Core of Thiopeptide Natural Products by Scalable Thiazole-Forming Reactions of Cysteine Derivatives and Nitriles

AbstractThe increased resistance of bacteria to clinical antibiotics is one of the major dilemmas facing human health and without solutions the problem will grow exponentially worse. Thiopeptide natural products have shown promising antibiotic activities and provide an opportunity for the development of a new class of antibiotics. Attempts to directly translate these compounds into human medicine have been limited due to poor physiochemical properties. The synthesis of the core structure of the 26-membered class of thiopeptide natural products is reported using chemistry that enables the synthesis of large quantities of synthetic intermediates and the common core structure. The use of cysteine/nitrile condensation reactions followed by oxidation to generate thiazoles has been key in enabling large academic scale reactions that in many instances avoided chromatography further aiding in accessing large amounts of key synthetic intermediates.

Synthesis and SAR of a series of mGlu7 NAMs based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinoline carboxylate core

A High-Throughput Screening (HTS) campaign identified a fundamentally new mGlu7 NAM chemotype, based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinolone carboxylate core. The initial hit, VU0226390, was a potent mGlu7 NAM (IC50 = 647 nM, 6% L-AP4 min) with selectivity versus the other group III mGlu receptors (>30 μM vs. mGlu4 and mGlu8). A multi-dimensional optimization effort surveyed all regions of this new chemotype, and found very steep SAR, reminiscent of allosteric modulators, and unexpected piperazine mimetics (whereas classical bioisosteres failed). While mGlu7 NAM potency could be improved (IC50s ~ 350 nM), the necessity of the ethyl ester moiety and poor physiochemical and DMPK properties precluded optimization towards in vivo tool compounds or clinical candidates. Still, this hit-to-lead campaign afforded key medicinal chemistry insights and new opportunities.

Amorphous nano morin outperforms native molecule in anticancer activity and oral bioavailability

In the past decade, naturally occurring phytoconstituents have emerged as potential therapeutic agents and alternative to synthetic drugs. However, efficient delivery of hydrophobic phytoconstituents into the body with desired therapeutic efficacy is a key challenge for the pharmaceutical industries due to their insolubility in water and low oral bioavailability. Nanosuspension formulations have shown promises to improve the delivery of the hydrophobic molecules with simultaneously avoiding the drawbacks like carrier toxicity and scale-up issues of other nanotechnology-based drug delivery systems. In this study, we have used morin hydrate (MH), a flavonol, and developed MH nanosuspension formulation (MHNS) to improve its poor physiochemical properties and low oral bioavailability. Different stabilizers with varying concentrations were investigated for preparing nanosuspension. MHNS was characterized by DLS, TEM, FTIR, DSC, powder XRD and was evaluated for its solubility, dissolution, partition coefficient, in-vitro anticancer activity and pharmacokinetics in rats. The optimized nanosuspension formulation, with a size of <100 nm, is capable of increasing aqueous solubility, dissolution rate, and oral bioavailability of MH. Moreover, the therapeutic efficacy, in terms of cytotoxicity to human lung cancer cells, of MH was also increased after formulating into nanosuspension form.

A study on improving tire pyrolysis oil quality by blending it with biodiesels derived from edible oils

Owing to the poor physio-chemical properties of tire pyrolysis oil, its application in diesel engines is limited. It is highly viscous, denser than diesel and has lesser calorific value. Its quality can be improved by blending it with any fuel that is less viscous. In this study, tire pyrolysis oil is blended with eight different biodiesels, derived from edible oils, to improve its quality and the effect of dilution on its properties is studied. Apparently, not all the biodiesels are good to be blended with it. Coconut and soy biodiesel bring in desirable and appreciable variations in its properties. But, the percentage change in viscosity is far greater in coconut-tire oil blends than soy-tire oil blends. It is concluded that the coconut biodiesel is the ideal biodiesel to be blended with tire oil to improve its quality acceptably, among all the chosen biodiesels produced from edible oils.

A scaffold replacement approach towards new sirtuin 2 inhibitors

Sirtuins (SIRT1–SIRT7) are an evolutionary conserved family of NAD+-dependent protein deacylases regulating the acylation state of ε-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.

Effects of Biochar Amendment on Soil Problems and Improving Rice Production under Salinity Conditions

Soil with poor physio-chemical and biological properties prevent plant growth. These poor characteristics may be due to soil creation processes, but also include largely inappropriate agricultural practices and/or anthropogenic pollution. During the last 4 decades, the world has lost one-third of its cropland due to pollution and erosion. Therefore, a series of operations is required to improve and recover the soil. Biochar is a new multifunctional carbon material extensively used as a modifier to improve soil quality and crop production. Previous studies have discussed the properties of biochar with varying soil pollutants and their effects on soil productivity and carbon sequestration. Comparatively, little attention has been paid to the effects of biochar application on rice growth in the problem of soils, especially in the saline-sodic soils. A comprehensive review of the literature with a high focusing on the effects of biochar application on problem soils and rice-growing under salinity conditions is needed. The present review gives an overview of the soil's problem, biochar amendment effects on physicochemical properties of soil, and how the biochar amendment could interact in soil microbes and root with remediation under salinity conditions for improving rice productivity. The findings of this review showed that biochar application can improve soil quality, reduce soil's problem and increase rice production under salinity conditions. It is anticipated that further researches on the biochar amendment will increase our understanding of the interactions of biochar with soil components, accelerate our attempts on soil remediation, and improve rice production under salinity conditions.

Abstract P5-04-07: GDC-9545: A novel ER antagonist and clinical candidate that combines desirable mechanistic and pre-clinical DMPK attributes

Abstract ER+ breast cancers depend on ER signaling throughout disease progression, including after acquired resistance to existing endocrine agents, providing a rationale for further optimization and development of ER-targeting agents. Fulvestrant is unique amongst currently approved ER ligand therapeutics due to its classification as a full ER antagonist, which is thought to be achieved through degradation of ERα protein. However, the full clinical potential of fulvestrant is believed to be limited by poor physiochemical properties and exposure limitations due to its administration by intramuscular injection. Strategies to generate orally bioavailable molecules that retain fulvestrant's full antagonist profile but with considerably improved drug-like properties are thus being widely employed to identify next generation ER therapeutics. However, we find that therapeutic candidates that have recently emerged from prospective optimization of ER degradation, including GDC-0810 and GDC-0927, are not mechanistically equivalent. GDC-0810, GDC-0927, and fulvestrant display unique profiles in terms of ER degradation, transcriptional phenotypes and anti-proliferative potential across a panel of ER+ breast cancer cell lines. In HCI-011 (ER.WT) and HCI-013 (ER.Y537S) ER+ patient-derived breast cancer xenograft (PDX) models, GDC-0927 achieves more robust transcriptional suppression of ER than GDC-0810, and also and greater efficacy. Although displaying a more desirable mechanistic profile than GDC-0810, GDC-0927 has more rapid clearance and poor oral bioavailability, leading to a high pill burden and potential exposure limitation. Here, we describe for the first time GDC-9545, in which the distinct liabilities of GDC-0810, GDC-0927 and fulvestrant are addressed. GDC-9545 is a non-steroidal ER ligand that is highly potent in competing with estradiol for binding and in driving an antagonist conformation within the ER ligand binding domain. Like fulvestrant, and displaying some improvements over GDC-0927, GDC-9545 consistently induces ER turnover and drives deep transcriptional suppression of ER, resulting in robust in vitro anti-proliferative activity. GDC-9545 exhibits reduced metabolism and increased oral bioavailability relative to GDC-0927, resulting in an overall improved oral exposure in multiple species. As a result of both its mechanistic pharmacology and improved oral exposure, GDC-9545 can achieve the same degree of anti-tumor activity as GDC-0927 but at 100-fold lower doses in the HCI-013 PDX model. The in vivo efficacy of GDC-9545 in this model is greater than GDC-0810 and fulvestrant at clinically relevant exposures. The highly potent in vivo efficacy of GDC-9545 likely arises due to the particular combination of high binding potency, full suppression of ER signaling, and an improved DMPK profile when compared to GDC-0927 and fulvestrant. GDC-9545 is currently being evaluated in Phase 1 clinical trials (ClinicalTrials.gov Identifier: NCT03332797). Citation Format: Metcalfe C, Ingalla E, Blake RA, Chang J, Daemen A, De Bruyn T, Giltnane JM, Guan J, Hafner M, Hartman S, Kategaya L, Kleinheinz T, Liang J, Mody V, Nannini M, Oeh J, Ubhayakar S, Wertz I, Young A, Zbieg J, Zhou W, Sampath D, Friedman LS, Wang X. GDC-9545: A novel ER antagonist and clinical candidate that combines desirable mechanistic and pre-clinical DMPK attributes [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-07.

TRPA1 ankyrin repeat six interacts with a small molecule inhibitor chemotype

TRPA1, a member of the transient receptor potential channel (TRP) family, is genetically linked to pain in humans, and small molecule inhibitors are efficacious in preclinical animal models of inflammatory pain. These findings have driven significant interest in development of selective TRPA1 inhibitors as potential analgesics. The majority of TRPA1 inhibitors characterized to date have been reported to interact with the S5 transmembrane helices forming part of the pore region of the channel. However, the development of many of these inhibitors as clinical drug candidates has been prevented by high lipophilicity, low solubility, and poor pharmacokinetic profiles. Identification of alternate compound interacting sites on TRPA1 provides the opportunity to develop structurally distinct modulators with novel structure-activity relationships and more desirable physiochemical properties. In this paper, we have identified a previously undescribed potent and selective small molecule thiadiazole structural class of TRPA1 inhibitor. Using species ortholog chimeric and mutagenesis strategies, we narrowed down the site of interaction to ankyrinR #6 within the distal N-terminal region of TRPA1. To identify the individual amino acid residues involved, we generated a computational model of the ankyrinR domain. This model was used predictively to identify three critical amino acids in human TRPA1, G238, N249, and K270, which were confirmed by mutagenesis to account for compound activity. These findings establish a small molecule interaction region on TRPA1, expanding potential avenues for developing TRPA1 inhibitor analgesics and for probing the mechanism of channel gating.

Fabrication of surfactant-stabilized nanosuspension of naringenin to surpass its poor physiochemical properties and low oral bioavailability

BackgroundNanosuspension is a biphasic system consisting of native drug particles dispersed in an aqueous surfactant or polymeric solution with a particle size between 10 to 1000 nm. In contrast to other drug delivery systems, nanosuspension offer the unique advantage of increasing solubility of the native drug resulting into faster drug absorption and hence achieving faster maximum plasma concentration. Hypothesis/PurposeThe present study aims to evaluate surfactants/polymer stabilized nanosuspensions of naringenin (NN), a phytomedicine, to surpass its poor physiochemical properties and low oral bioavailability. Study designOptimization and characterization (DLS, SEM, PXRD and DSC) of nanosuspensions followed by in-vitro drug dissolution studies and pharmacokinetic study in male Sprague–Dawley rats were performed. MethodsNanosuspensions were prepared by precipitation-ultrasonication method with varying concentrations of different surfactants and polymer such as sodium cholate (SC), sodium lauryl sulphate (SLS), poly ethylene glycol 4000 (PEG), polysorbate 80 (Tween® 80), poloxomer-188 and D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS or Vitamin E-TPGS). ResultsNanosuspension prepared with 0.5% w/v d-α-Tocopherol polyethylene glycol 1000 succinate (TPNS) and 7.5 mg NN, showed the smallest size of 118.1 ± 2.7 nm. TPNS showed increase in drug dissolution in simulated gastric fluid pH 1.2 (SGF) and phosphate buffer pH 6.8 (PB). TPNS demonstrated an improved pharmacokinetic profile compared to pure NN resulting 2.14 and 3.76 folds increase in Cmax and AUC, respectively. In addition, TPNS were stable over a period of six months. ConclusionThe developed formulation strategy of nanosuspension could be exploited to improve the solubility and bio-availability of poorly soluble NN and other phytomedicines.

Growth and yield response of lettuce to irrigation and growth media from composted sawdust and rice husk

ABSTRACTIn sub-Saharan Africa, manure and loam soil are popular growing media substrates. However, their poor physiochemical properties limit their use in growing media. Following a survey of farmers, single species sawdust, mixed species sawdust, and rice husk (RH) were selected and composted with poultry manure. Additionally, the RH was charred for use in soilless media. Objectives were to produce feedstock-specific composts and determine appropriate proportion for using them in containerized systems. Three composts produced were amended with soil in ratios of 1:1, 1:2, and 1:3 (v/v) in an initial experiment. In a second experiment (soilless), the single sawdust and RH compost were each amended with RH biochar in ratios of 1:0, 1:1, 1:2 (v/v) and subjected to half or full pot irrigation. RH compost amended soils gave the highest lettuce yield. In the soilless media, 2:1 ratio (v/v) of biochar to sawdust compost gave the highest yield.

Opposites attract in bispecific antibody engineering

Bispecific antibodies show great promise as intrinsic combination therapies, but often suffer from poor physiochemical properties, many times related to poor heterodimerization. De Nardis et al. identify specific electrostatic interactions that facilitate efficient heterodimerization, resulting in bispecific antibodies with physiochemical properties very similar to those of naturally occurring antibodies. This provides a new platform for the treatment of an array of diseases from cancer and autoimmune diseases to infectious diseases.

Abstract 2745: Pharmacological characterisation of cell active inhibitors of Poly(ADP-ribose) glycohydrolase (PARG)

Abstract Poly(ADP-ribose) glycohydrolase (PARG) is the only enzyme known to catalyse hydrolysis of the O-glycosidic linkages of ADP-ribose polymers, thereby reversing the effects of poly(ADP-ribose) polymerases. Total PARG deficiency leads to cell death whilst PARG depletion, using RNAi, leads to pleiotropic effects such as PAR chain persistence, progression of single- to double-strand DNA lesions and NAD+ depletion. Whilst efforts to develop small molecule inhibitors of PARG activity have generally been hampered by poor physiochemical properties, off-target pharmacology and a lack of cell permeability, we have now developed a series of PARG inhibitors which have proved to be useful biological tool compounds. Displaying selective activity in both biochemical and, more importantly, cellular assays of PARG function, these derivatives have allowed an exploration of the phenotypes resulting from reversible, pharmacological PARG inhibition. Citation Format: Dominic James, Allan Jordan, Nicola Hamilton, Alison McGonagle, Kate Smith, Alexandra Stowell, Ian Waddell, Bohdan Waszkowycz, Donald Ogilvie. Pharmacological characterisation of cell active inhibitors of Poly(ADP-ribose) glycohydrolase (PARG). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2745. doi:10.1158/1538-7445.AM2014-2745

Dual-targeting Janus Dendrimer Based Peptides for Bone Cancer: Synthesis and Preliminary Biological Evaluation

The development of dual-targeting drug delivery system is helpful to overcome the poor physiochemical properties of chemotherapeutic agents. The RGD sequence has a potential dual-targeting property, with which the chemotherapeutic agents can be delivered to bone tissue and tumor. And the Janus dendrimer which consists of two dendrons with different tasks is useful for improving the effect of polymer on pharmacokinetic properties. In this paper, a Janustype peptide dendrimer which consisted of RGD dimer and 5-FU dimer was synthesized and well characterized by 1H NMR and MS techniques, as well as the other three compounds for contrast. The hydroxyapatite binding assay and drug release study were evaluated. The Janus-type dendrimer with both enhanced targeting property and optimized release property, may reduce the side effects in normal tissues and have potential sustained-release effect. Thus, it may represent a novel opportunity to apply the versatile Janus-type dual-targeting delivery system to applications in bone tumor treatment. Keywords: Bone cancer, dual-targeting, hydroxyapatite, in vitro, Janus dendrimer, peptide, RGD.

Dual-targeting delivery system for bone cancer: synthesis and preliminary biological evaluation

Chemotherapy in treatment of malignant tumors has many side effects due to the poor physiochemical properties and the toxicity to normal tissues. The dual-targeting drug delivery system combining two high-affinity ligands can target anticancer drug primary to the diseased tissue, then to the tumor, which provides both greater efficacy of treatment and less harm to normal tissues. In this paper, a novel dual-targeting moiety RGD7 (R-G-D-D-D-D-D-D-D; Nonapeptide for bone cancer combining D6 peptide as bone target moiety and RGD peptide as tumors target moiety was contracted. A series of bone and/or tumor targeting conjugates have been synthesized in a convergent approach and well characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS) techniques. The hydroxyapatite (HAP) binding, water solubility, the drug release and the distribution in vivo were evaluated. All the conjugates were water-soluble and able to release the parent drugs in vitro. The bone-targeting property of the dual-targeting delivery system was enhanced from the results of the HAP binding and the distribution in vivo. The experiment for verifying tumor targeting property was underway. These results provided an effective entry to the development of a new dual-targeting delivery system for bone cancer.

Discovery of a Novel Chemical Class of mGlu5 Allosteric Ligands with Distinct Modes of Pharmacology

We previously discovered a positive allosteric modulator (PAM) of the metabotropic glutamate receptor subtype 5 (mGlu5) termed 4 N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) that elicits receptor activation through a novel allosteric site on mGlu5, distinct from the classical mGlu5 negative allosteric modulator (NAM) MPEP allosteric site. However, a shallow structure−activity relationship (SAR), poor physiochemical properties, and weak PAM activity at rat mGlu5 limited the utility of CPPHA to explore allosteric activation of mGlu5 at a non-MPEP site. Thus, we performed a functional high-throughput screen (HTS) and identified a novel mGlu5 PAM benzamide scaffold, exemplified by VU0001850 (EC50 = 1.3 μM, 106% Glumax) and VU0040237 (EC50 = 350 nM, 84% Glu Max). An iterative parallel synthesis approach delivered 22 analogues, optimized mGlu5 PAM activity to afford VU0357121 (EC50 = 33 nM, 92% Glumax), and also revealed the first non-MPEP site neutral allosteric ligand (VU0365396). Like CPPHA, PAMs within this class do not appear to bind at the MPEP allosteric site based on radioligand binding studies. Moreover, mutagenesis studies indicate that VU0357121 and related analogues bind to a yet uncharacterized allosteric site on mGlu5, distinct from CPPHA, yet share a functional interaction with the MPEP site.

Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs

Epoxyeicosatrienoic acids that have anti-hypertensive and anti-inflammatory properties are mainly metabolized by soluble epoxide hydrolase (sEH, EC 3.3.2.3). Therefore, sEH has emerged as a therapeutic target for treating various cardiovascular diseases and inflammatory pain. N,N'-Disubstituted ureas are potent sEH inhibitors in vitro. However, in vivo usage of early sEH inhibitors has been limited by their low bioavailability and poor physiochemical properties. Therefore, a group of highly potent compounds with more drug-like physiochemical properties were evaluated by monitoring their plasma profiles in dogs treated orally with sEH inhibitors. Urea compounds with an adamantyl or a 4-trifluoromethoxyphenyl group on one side and a piperidyl or a cyclohexyl ether group on the other side of the urea function showed pharmacokinetic profiles with high plasma concentrations and long half lives. In particular, the inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) not only is very potent with good physiochemical properties, but also shows high oral bioavailability for doses ranging from 0.01 to 1mg/kg. This compound is also very potent against the sEH of several mammals, suggesting that t-AUCB will be an excellent tool to evaluate the biology of sEH in multiple animal models. Such compounds may also be a valuable lead for the development of veterinary therapeutics.