BACKGROUND:Avenciguat, a potent nitric oxide-independent activator of soluble guanylyl cyclase, is being evaluated in chronic kidney disease and systemic sclerosis. We assessed avenciguat absolute bioavailability and mass balance. RESEARCH DESIGN AND METHODS:Open-label Phase 1 trial in healthy men. Doses: Part A, 3 mg [14C]-avenciguat single dose (oral solution); Part B, 3 mg unlabeled avenciguat (tablet) then 30 µg [14C]-avenciguat (intravenous). Primary endpoints: Part A, mass balance and recovery of [14C] radioactivity in excreta; Part B, absolute bioavailability. Safety and pharmacokinetics were evaluated. RESULTS:In Part A (N = 6), geometric mean recovery of [14C] radioactivity was 90.0% (range 80.6-96.0%). Elimination was mainly via feces (geometric mean 85.3%; range 76.5-91.3%); urine (4.66%; range 4.10-5.31%). In Part B (N = 6), the absolute bioavailability of avenciguat was 83.0%. In pooled plasma, the predominant drug-related component was avenciguat (mean 86.8%); the acyl glucuronide metabolite represented 5.2% of radioactivity. Drug-related adverse events (AEs) occurred in 33.3% (4/12) of participants, mostly mild, with one moderate presyncope event. No AEs leading to discontinuation were reported. CONCLUSIONS:Avenciguat was generally well tolerated and was primarily excreted unchanged in feces and minimally excreted in urine. After oral administration, avenciguat has high oral bioavailability. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov (NCT05515328).

Background: Pharmacokinetic drug–drug interactions (DDIs) can be caused by the effect of a pharmaceutical compound on the activity of one or more subtypes of the Cytochrome P450 (CYP) family, UDP-glucuronosyltransferases (UGTs), and/or transporters. As the number of therapeutic areas with polypharmacy has increased, interest has grown in assessing the risk of DDIs during the early phases of drug development. Various lines of research have led to improved mathematical models to predict DDIs, culminating in the Food and Drug Administration’s (FDA) guidelines on evaluating pharmacokinetic DDI risks. However, the recommended static models are highly conservative and often result in false positive predictions. The current research aims to improve the workflow for assessing CYP-mediated DDI risk using Boehringer Ingelheim (BI) proprietary compounds. Methods: The Drug–drug Interaction Risk Calculator (PharmaPendium) was used to evaluate the mechanistic static model, and predictions were correlated with human pharmacokinetic studies from Phase I clinical trials. Results: The results demonstrated that the FDA formula performed well in predicting DDIs for BI proprietary compounds. Furthermore, the integration of either human renal excretion or preclinical species total excretion data into the mechanistic static model enhanced the predictive performance for candidate drugs as victims in DDIs. Conclusions: The basic static models (BSMs) for drug interactions should be used in early drug discovery to “rule out” DDI risks because of the minimal inputs required and the low rate of false negative predictions. Mechanistic static models (MSMs) can then be implemented for compounds that require additional evaluation.

Zongertinib is a potent irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing EGFR, thereby limiting associated toxicities. Zongertinib is being evaluated as monotherapy for patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 mutations. The objectives of this non-randomized, open-label, two-part, Phase I study were to assess the absorption, distribution, metabolism and excretion (ADME) of zongertinib (Part A) and the absolute bioavailability (F) of oral zongertinib compared with intravenous (IV) microtracer infusion (Part B), in healthy male volunteers. In the first part (ADME assessment), eight subjects received a single oral dose of 60 mg (C-14)-zongertinib solution (containing radiolabeled [14C]-zongertinib [3.7 MBq] and unlabeled zongertinib). In the second part (F assessment), seven subjects received an oral dose of unlabeled zongertinib (60 mg film-coated tablet) after an overnight fast, followed by a 15-minute IV microtracer infusion of (C-14)-zongertinib solution 100 μg, containing 10 μg of [14C]-zongertinib [∼0.03 MBq] and 90 μg of unlabeled zongertinib. The maximum plasma concentration of oral zongertinib solution was reached at a median of 1-h post-dose (range 0.5‒2.0 h). Mean recovery of the radioactive dose was 93.8% (92.5% in feces and 1.30% in urine). Unchanged zongertinib represented most of the circulating radioactivity in plasma (74.6%) and was the predominant excreted component in feces (31.4% of the administered dose). In contrast, only trace levels of zongertinib were detected in urine (0.18% of the dose). A significant portion of unchanged zongertinib detected in feces may result from the de-conjugation of conjugated metabolites in the gut. The major metabolic pathways involved oxidation and to a lesser extent glucuronidation and glutathione conjugation. The two most abundant circulating metabolites were M551(1) (mono-oxidation) and M656(1) (cysteine conjugate), representing 5.7% and 2.5% of total radioactivity over the 168-hour collection period (AUC0-168h), respectively. The mean F of the tablet-form zongertinib was 76.2% with low intra-individual variability. Following the IV dose, zongertinib had a low plasma clearance of 106 mL/min and the apparent volume of distribution was 138 L. Zongertinib has a manageable safety profile in both parts of the study. Zongertinib was rapidly absorbed with high absolute bioavailability. Unchanged zongertinib was the predominant component without any major metabolite circulating in plasma. Zongertinib was metabolized via oxidation, glucuronidation, and glutathione conjugation. Zongertinib was primarily excreted via feces, with minimal renal excretion. David Joseph, Rolf Grempler, Guanfa Gan, Adam Auclair, Hlaing Maw, Ralf Laux, Ralf Kiesling, Sven Wind, David Minch. Absorption, distribution, metabolism and excretion (ADME) properties and absolute bioavailability of zongertinib, a selective oral HER2-specific tyrosine kinase inhibitor, in healthy male subjects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB270.

Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits human epidermal growth factor receptor 2 (HER2) while sparing epidermal growth factor receptor (EGFR), minimizing related toxicities. This non-randomized, open-label, Phase I study evaluated the absorption, distribution, metabolism and excretion (ADME) of zongertinib (Part A) and its absolute bioavailability (F) (Part B) in healthy male volunteers. In Part A, eight subjects received a single oral 60 mg dose of zongertinib (C-14)-solution containing radiolabeled [14C]zongertinib [3.7 MBq] and unlabeled drug. In Part B, seven subjects received an oral unlabeled zongertinib 60-mg film-coated tablet after fasting, followed by a 15-min intravenous (IV) infusion of 100 μg zongertinib solution (C-14), consisting of 10 μg [14C]zongertinib [ 0.03 MBq] and 90 μg unlabeled drug. Plasma pharmacokinetics, excretion pathways, metabolism, and bioavailability were assessed. Safety was evaluated in both study parts. After oral dosing in Part A, peak plasma concentration occurred at a median of 1-h post-dose (range 0.5‒2.0 h). Mean recovery of the radioactive dose was 93.8

BACKGROUND:Dabigatran etexilate, a direct oral thrombin inhibitor, is approved to treat venous thromboembolism (VTE) in both adults and children.OBJECTIVES:This population analysis characterized relationships between dabigatran total plasma concentrations and coagulation laboratory parameters (activated partial thromboplastin time [aPTT]; diluted thrombin time [dTT]; ecarin clotting time [ECT]).METHODS:Data from three phase 2a and one single-arm and one randomized, comparative phase 2b/3 pediatric studies (measurements: aPTT 2,925 [N = 358]; dTT 2,348 [N = 324]; ECT 2,929 [N = 357]) were compared with adult data (5,740 aPTT, 3,472 dTT, 3,817 ECT measurements; N = 1,978). Population models were fitted using nonlinear mixed-effects modeling. Covariates (e.g., sex, age) were assessed on baseline and drug-effect parameters, using a stepwise covariate model-building procedure.RESULTS:Overall, relationships between dabigatran, aPTT, dTT, and ECT were similar in children and adults. For children aged <6 months, a higher proportion of baseline samples were outside or close to the upper aPTT and ECT adult ranges. No age-related differences were detected for dTT. With increasing dabigatran concentration, aPTT rose nonlinearly (half the maximum effect at 368 ng/mL dabigatran) while dTT and ECT increased linearly (0.37 and 0.73% change per ng/mL dabigatran, respectively). Mean baseline aPTT (45 vs. 36 seconds) and ECT (40 vs. 36 seconds) were slightly increased for those aged <6 months versus older children.CONCLUSION:The similar relationships of laboratory parameters observed across pediatric age groups suggests that developmental changes in the hemostatic system may have little effect on response to dabigatran.

The interleukin-36 signalling pathway is associated with pathogenesis of a number of inflammatory diseases. Spesolimab is a selective, humanised, IgG1 antibody that targets the interleukin-36 receptor. We aimed to evaluate the pharmacokinetics, safety and tolerability of single and multiple doses of spesolimab in healthy non-Japanese and Japanese subjects. Five phase I clinical studies (three placebo-controlled dose-escalation, two open-label) were conducted in healthy volunteers; single or multiple doses of spesolimab were administered by intravenous infusion or subcutaneous injection. Plasma samples were collected to investigate the pharmacokinetics of spesolimab and evaluate changes with respect to dose, frequency of dosing, formulation and injection site. Immunogenicity, safety and tolerability were also assessed. Intravenous spesolimab exhibited target-mediated drug disposition at low doses (0.01–0.3 mg/kg) and linear kinetics at doses ≥ 0.3 mg/kg. Steady state was not attained after the fourth weekly dose because of the long half-life (3–5 weeks). Bioavailability of subcutaneous spesolimab increased with increasing dose over the range of 150–600 mg and was higher when administered to the thigh than to the abdomen. The pharmacokinetic profile was consistent between Japanese and non-Japanese subjects. Positive anti-drug antibody responses occurred during the terminal phase of the spesolimab concentration–time profile in 26.7–33.3

Background Dabigatran etexilate (DE), a direct oral thrombin inhibitor, has been evaluated in children with venous thromboembolism (VTE) using oral solution, pellets, or capsules. Objectives This study evaluated DE pharmacokinetics (PK) in children with VTE and the appropriateness of a DE pediatric age- and weight-based dosing algorithm. Patients/Methods A population PK model was fitted to data from four single-arm and one randomized, comparative pediatric VTE studies (358 children aged birth to <18 years; 2748 PK observations) and one healthy-adult study (32 males aged <40 years; 1523 PK observations) using nonlinear mixed-effects modeling. A stepwise, covariate, model-building procedure evaluated the influence of covariates (e.g., age, body weight, body surface area [BSA]-normalized renal function, and sex). The final model was used to evaluate the pediatric dosing algorithm, with simulations comparing pediatric trough exposure with reference exposure defined for the pediatric studies. Results The population PK of dabigatran was adequately described by a two-compartment model with first-order elimination and absorption. Age, weight, BSA-normalized renal function, and sex were statistically significant covariates (all P < .05). Apparent clearance increased with age (independently of body weight), diminished with decreasing BSA-normalized renal function, and was lower in females than males. All disposition parameters increased with body weight escalation (allometric scaling). Simulations confirmed that for all DE formulations, the final pediatric dosing algorithms achieved reference exposure without dose adjustment. Conclusions Using a population PK model of DE for children with VTE, simulations showed that the final dosing algorithms were appropriate for all DE formulations; no dose titration was needed.

Accurate prediction of the human pharmacokinetics (PK) of a candidate monoclonal antibody from nonclinical data is critical to maximize the success of clinical trials. However, for monoclonal antibodies exhibiting nonlinear clearance due to target-mediated drug disposition, PK predictions are particularly challenging. That challenge is further compounded for molecules lacking cross-reactivity in a nonhuman primate, in which case a surrogate antibody selective for the target in rodent may be required. For these cases, prediction of human PK must account for any interspecies differences in binding kinetics, target expression, target turnover, and potentially epitope. We present here a model-based method for predicting the human PK of MAB92 (also known as BI 655130), a humanized IgG1 κ monoclonal antibody directed against human IL-36R. Preclinical PK was generated in the mouse with a chimeric rat anti-mouse IgG2a surrogate antibody cross-reactive against mouse IL-36R. Target-specific parameters such as antibody binding affinity (KD), internalization rate of the drug target complex (kint), target degradation rate (kdeg), and target abundance (R0) were integrated into the model. Two different methods of assigning human R0 were evaluated: the first assumed comparable expression between human and mouse and the second used high-resolution mRNA transcriptome data (FANTOM5) as a surrogate for expression. Utilizing the mouse R0 to predict human PK, AUC0-∞ was substantially underpredicted for nonsaturating doses; however, after correcting for differences in RNA transcriptome between species, AUC0-∞ was predicted largely within 1.5-fold of observations in first-in-human studies, demonstrating the validity of the modeling approach. Our results suggest that semi-mechanistic models incorporating RNA transcriptome data and target-specific parameters may improve the predictivity of first-in-human PK.

Exploring various cyclization strategies, using a submicromolar pyrazole HTS screening hit 6 as a starting point, a novel indazole based CCR1 antagonist core was discovered. This report presents the design and SAR of CCR1 indazole and azaindazole antagonists leading to the identification of three development compounds, including 19e that was advanced to early clinical trials.

Objective To evaluate the safety, efficacy and therapeutic mechanism of BI 655064, an antagonistic anti-CD40 monoclonal antibody, in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR). Methods In total, 67 patients were randomised to receive weekly subcutaneous doses of 120 mg BI 655064 (n=44) or placebo (n=23) for 12 weeks. The primary endpoint was the proportion of patients who achieved 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Safety was assessed in patients who received at least one dose of study drug. Results At week 12, the primary endpoint was not met, with 68.2% of patients treated with BI 655064 achieving an ACR20 vs 45.5% with placebo (p=0.064); using Bayesian analysis, the posterior probability of seeing a difference greater than 35% was 42.9%. BI 655064 was associated with greater changes in CD40–CD40L pathway-related markers, including reductions in inflammatory and bone resorption markers (interleukin-6, matrix metalloproteinase-3, receptor activator of nuclear factor-κB ligand), concentration of autoantibodies (immunoglobulin [Ig]G rheumatoid factor [RF], IgM RF, IgA RF) and CD95+ activated B-cell subsets. No serious adverse events (AEs) related to BI 655064 treatment or thromboembolic events occurred; reported AEs were mainly of mild intensity. Conclusion Although blockade of the CD40–CD40L pathway with BI 655064 in MTX-IR patients with RA resulted in marked changes in clinical and biological parameters, including reductions in activated B-cells, autoantibody production and inflammatory and bone resorption markers, with a favourable safety profile, clinical efficacy was not demonstrated in this small phase IIa study. Trial registration number NCT01751776

BI 655064 is a humanized antagonistic anti-cluster of differentiation (CD) 40 monoclonal antibody that selectively blocks the CD40-CD40L interaction. The CD40-CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and lupus nephritis. The safety, tolerability, pharmacokinetics, and pharmacodynamics of repeated once-weekly BI 655064 subcutaneous dosing over 4 weeks were evaluated in a multiple-dose study in healthy subjects. Subjects (N = 40) were randomized 4:1 to four sequential BI 655064 dose groups (80, 120, 180, 240 mg) or to placebo. Safety and tolerability, plasma exposure, CD40 receptor occupancy, and CD40L-induced CD54 upregulation were assessed over 64 and 78 days for the 80- to 180-mg and 240-mg dose groups, respectively. BI 655064 exposure increased in a supraproportional manner, due to target-mediated drug clearance, for doses between 80 mg and 120 mg, but was near proportional for doses greater than 120 mg. Terminal half-life ranged between 6 and 8 days. Dose-dependent accumulation of BI 655064 supports the use of a loading dose in future clinical studies. Following 4 weeks of dosing, >90% CD40 receptor occupancy and inhibition of CD54 upregulation were observed at all dose levels, lasting for 17 days after the last dose. BI 655064 was generally well tolerated. There were no serious adverse events and the frequency and intensity of adverse events were similar for BI 655064 and placebo; no dose relationship or relevant signs of an acute immune reaction were observed. These findings support further investigation of BI 655064 as a potential treatment for autoimmune diseases.

The CD40–CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and lupus nephritis. The safety, pharmacokinetics and pharmacodynamics of BI 655064, a novel humanised antagonistic anti-CD40 monoclonal antibody, were investigated in this first-in-human trial.

A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties.

Background The CD40-CD40L pathway may play a major role in autoimmune disorders like rheumatoid arthritis (RA). Blocking this pathway may be a promising new treatment for RA-patients. BI 655064 is a novel humanized antagonistic anti-CD40 monoclonal antibody, free of agonistic activity and without antibody-dependent cellular- or complement-dependent cytotoxicity. BI 655064 binds human CD40 on B cells in whole blood with an EC90 of 6.85±0.74 nM. Objectives BI 655064 was investigated in healthy volunteers to assess safety, tolerability, PK and PD after single and multiple dosing. Methods In a single-blinded randomized, placebo-controlled trial in healthy subjects, BI 655064 was administered to 72 male subjects in increasing single doses of 0.2-120 mg i.v. and 40-120 mg s.c. A double-blinded multiple rising dose study was conducted in 40 male and female subjects at doses of 80-240 mg q1w s.c. for 4 weeks. Blood samples were analyzed for PK, CD40-receptor occupancy (RO) and inhibition of CD40L-induced CD54-upregulation throughout the entire trial duration. Results All doses of BI 655064 were well tolerated in both studies. There was no-drug related serious adverse event (AE) or significant AE reported. Reported AEs were mainly of mild intensity and did not show a dose-relationship. There was no significant difference in the total number of subjects with AE [BI 655064: 47/86 (54%) vs. placebo: 16/26 (61%)] or category of reported AEs between subjects treated with BI 655064 or placebo (combined data from both studies). The most frequently reported AEs were headache (BI 655064 23% vs. placebo 19%) and upper respiratory tract infection (BI 655064 13% vs placebo 12%) in both studies (combined data). There was no evidence of thromboembolism or bleeding, no hypersensitivity reaction, no cytokine release and no relevant change in safety laboratory tests including coagulation parameters. BI 655064 plasma exposure increased in a supra-proportional manner indicating target mediated drug clearance with a terminal half-life ranging between 6 and 13 days. At single i.v. doses of 20 mg and higher, there was >90% RO and >90% inhibition of CD40L-induced CD54 upregulation for 24 hours after dosing. Single doses of 120 mg i.v. or s.c resulted in >90% RO and >90% inhibition of CD54 upregulation for at least one week. After multiple dosing, persistent >90% RO and >90% inhibition of CD40L-induced CD54 upregulation was maintained for the entire treatment period and for 3 weeks after the last dose for all doses of 120 mg q1w and above. Conclusions Early trials with BI 655064 show a favorable clinical safety profile and high potential to block the CD40-CD40L pathway supporting clinical trials with BI 655064 in RA-patients. Disclosure of Interest C. Schwabe Employee of: Auckland Clinical Studies, F. Wagner Employee of: Charité Research Institute, I. Filler Employee of: Charité Research Institute, M. Albulescu Employee of: Boehringer-Ingelheim, P. Rose Employee of: Boehringer-Ingelheim, B. Emerson Employee of: Boehringer-Ingelheim, T. Doan Employee of: Boehringer-Ingelheim, B. Rosenstock Employee of: Boehringer-Ingelheim, D. Joseph Employee of: Boehringer-Ingelheim, J. Hilbert Employee of: Boehringer-Ingelheim, C. Schölch Employee of: Boehringer-Ingelheim, J. Habeck Employee of: Boehringer-Ingelheim, R. Thiedmann Employee of: Boehringer-Ingelheim, S. Padula Employee of: Boehringer-Ingelheim, J. Steffgen Employee of: Boehringer-Ingelheim

ABSTRACT The effects of steady-state faldaprevir on the safety, pharmacokinetics, and pharmacodynamics of steady-state methadone and buprenorphine-naloxone were assessed in 34 healthy male and female subjects receiving stable addiction management therapy. Subjects continued receiving a stable oral dose of either methadone (up to a maximum dose of 180 mg per day) or buprenorphine-naloxone (up to a maximum dose of 24 mg-6 mg per day) and also received oral faldaprevir (240 mg) once daily (QD) for 8 days following a 480-mg loading dose. Serial blood samples were taken for pharmacokinetic analysis. The pharmacodynamics of the opioid maintenance regimens were evaluated by the objective and subjective opioid withdrawal scales. Coadministration of faldaprevir with methadone or buprenorphine-naloxone resulted in geometric mean ratios for the steady-state area under the concentration-time curve from 0 to 24 h (AUC 0–24,ss ), the steady-state maximum concentration of the drug in plasma ( C max,ss ), and the steady-state concentration of the drug in plasma at 24 h ( C 24,ss ) of 0.92 to 1.18 for ( R )-methadone, ( S )-methadone, buprenorphine, norbuprenorphine, and naloxone, with 90% confidence intervals including, or very close to including, 1.00 (no effect), suggesting a limited overall effect of faldaprevir. Although individual data showed moderate variability in the exposures between subjects and treatments, there was no evidence of symptoms of opiate overdose or withdrawal either during the coadministration of faldaprevir with methadone or buprenorphine-naloxone or after faldaprevir dosing was stopped. Similar faldaprevir exposures were observed in the methadone- and buprenorphine-naloxone-treated subjects. In conclusion, faldaprevir at 240 mg QD can be coadministered with methadone or buprenorphine-naloxone without dose adjustment, although given the relatively narrow therapeutic windows of these agents, monitoring for opiate overdose and withdrawal may still be appropriate. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637922.)

Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor and an inhibitor of UDP-glucuronosyltransferase-1A1 (UGT1A1), which is involved in raltegravir clearance. Raltegravir, an HIV integrase inhibitor, may be used in combination with HCV treatment in HCV/HIV co-infected patients. In this open-label, 2-period, fixed-sequence study, 24 healthy volunteers (12 males) received faldaprevir 240 mg and raltegravir 400 mg in 2 treatment schedules (A and B) separated by a washout phase of ≥7 days: (A) twice-daily raltegravir (Days 1-3), once-daily raltegravir (Day 4); (B) twice-daily raltegravir and twice-daily faldaprevir (loading dose, Day 1), twice-daily raltegravir and once-daily faldaprevir (Days 2-5), once-daily raltegravir and once-daily faldaprevir (Day 6). Pharmacokinetics and safety were assessed over 132 hours post-dosing. Compared with raltegravir alone, co-administration with faldaprevir led to 2.7-fold and 2.5-fold increases in raltegravir geometric mean AUC(τ,ss) and C(max,ss), respectively, and a similar increase in raltegravir glucuronide metabolite exposure. No serious adverse events (AEs) were reported and no subject discontinued due to AEs. Faldaprevir and raltegravir co-administration was well tolerated and resulted in a moderate increase in raltegravir exposure.

Inhibition of soluble epoxide hydrolase (sEH) is hypothesized to lead to an increase in circulating levels of epoxyeicosatrienoic acids, resulting in the potentiation of their in vivo pharmacological properties. As part of an effort to identify inhibitors of sEH with high and sustained plasma exposure, we recently performed a high throughput screen of our compound collection. The screen identified N-(3,3-diphenyl-propyl)-nicotinamide as a potent inhibitor of sEH. Further profiling of this lead revealed short metabolic half-lives in microsomes and rapid clearance in the rat. Consistent with these observations, the determination of the in vitro metabolic profile of N-(3,3-diphenyl-propyl)-nicotinamide in rat liver microsomes revealed extensive oxidative metabolism and a propensity for metabolite switching. Lead optimization, guided by the analysis of the solid-state costructure of N-(3,3-diphenyl-propyl)-nicotinamide bound to human sEH, led to the identification of a class of potent and selective inhibitors. An inhibitor from this class displayed an attractive in vitro metabolic profile and high and sustained plasma exposure in the rat after oral administration.