ABSTRACT
ABSTRACT: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/µL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/µL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.
Subject(s)
Immunologic Deficiency Syndromes , Primary Immunodeficiency Diseases , Receptors, CXCR4 , Warts , Humans , Female , Receptors, CXCR4/antagonists & inhibitors , Male , Primary Immunodeficiency Diseases/drug therapy , Warts/drug therapy , Double-Blind Method , Adult , Middle Aged , Immunologic Deficiency Syndromes/drug therapy , Quinolines/adverse effects , Quinolines/administration & dosage , Quinolines/therapeutic use , Adolescent , Young Adult , Child , Lymphocyte Count , Aminoquinolines , Benzimidazoles , ButylaminesABSTRACT
Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome is a rare primary immunodeficiency predominantly caused by heterozygous gain-of-function mutations in CXCR4 C-terminus. We assessed genotype-phenotype correlations for known pathogenic CXCR4 variants and in vitro response of each variant to mavorixafor, an investigational CXCR4 antagonist. We used cell-based assays to analyze CXCL12-induced receptor trafficking and downstream signaling of 14 pathogenic CXCR4 variants previously identified in patients with WHIM syndrome. All CXCR4 variants displayed impaired receptor trafficking, hyperactive downstream signaling, and enhanced chemotaxis in response to CXCL12. Mavorixafor inhibited CXCL12-dependent signaling and hyperactivation in cells harboring CXCR4WHIM mutations. A strong correlation was found between CXCR4 internalization defect and severity of blood leukocytopenias and infection susceptibility, and between AKT activation and immunoglobulin A level and CD4+ T-cell counts. This study is the first to show WHIM syndrome clinical phenotype variability as a function of both CXCR4WHIM genotype diversity and associated functional dysregulation. Our findings suggest that CXCR4 internalization may be used to assess the pathogenicity of CXCR4 variants in vitro and also as a potential WHIM-related disease biomarker. The investigational CXCR4 antagonist mavorixafor inhibited CXCL12-dependent signaling in all tested CXCR4-variant cell lines at clinically relevant concentrations.
Subject(s)
Agammaglobulinemia , Immunologic Deficiency Syndromes , Neutropenia , Warts , Agammaglobulinemia/genetics , Aminoquinolines , Benzimidazoles , Biomarkers , Butylamines , Genetic Association Studies , Humans , Immunoglobulin A/genetics , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/metabolism , Immunologic Deficiency Syndromes/pathology , Neutropenia/genetics , Neutropenia/metabolism , Primary Immunodeficiency Diseases , Proto-Oncogene Proteins c-akt/genetics , Receptors, CXCR4/genetics , Receptors, CXCR4/metabolism , Warts/genetics , Warts/metabolism , Warts/pathologyABSTRACT
Reducing the production of larger aggregation-prone amyloid ß-peptides (Aß) remains an untested therapeutic approach for reducing the appearance and growth of Aß plaques in the brain, which are a hallmark pathological feature of Alzheimer's disease. γ-Secretase modulators (GSMs) are therapeutics that impact γ-secretase-dependent cleavage of amyloid precursor protein to promote the production of shorter Aß peptides that are less prone to aggregation and plaque deposition. This is accomplished without inhibiting overall γ-secretase function and cleavage of other substrates, which is believed to be a source of deleterious side effects. Here, we report the pharmacokinetic and pharmacodynamic properties of BIIB042, a novel bioavailable and brain-penetrant GSM. In cell-based assays, BIIB042 reduced the levels of Aß42, increased the levels of Aß38 and had little effect on the levels of Aß40, the most abundant Aß species. Similar pharmacodynamic properties were confirmed in the central nervous system and in plasma of mice and rats, and also in plasma of cynomolgus monkeys after a single oral dose of BIIB042. BIIB042 reduced Aß42 levels and Aß plaque burden in Tg2576 mice, which overexpress human amyloid precursor protein and serve as a model system for Alzheimer's disease. BIIB042 did not inhibit cleavage of other γ-secretase substrates in cell-based and in vivo signaling and cleavage assays. The pharmacodynamic effects of lowering Aß42 in the central nervous system coupled with demonstrated efficacy in reducing plaque pathology suggests modulation of γ-secretase, with molecules like BIIB042, is a compelling therapeutic approach for the treatment of Alzheimer's disease.
Subject(s)
Aldehydes/pharmacokinetics , Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Brain/drug effects , Brain/enzymology , Aldehydes/administration & dosage , Amyloid beta-Peptides/blood , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Macaca fascicularis , Male , Mice , Plaque, Amyloid/metabolism , Protein Isoforms/blood , Rats , Rats, Inbred F344ABSTRACT
RORγt is a pivotal regulator of a pro-inflammatory gene expression program implicated in the pathology of several major human immune-mediated diseases. Evidence from mouse models demonstrates that genetic or pharmacological inhibition of RORγ activity can block the production of pathogenic cytokines, including IL-17, and convey therapeutic benefit. We have identified and developed a biaryl-carboxylamide series of RORγ inverse agonists via a structure based design approach. Co-crystal structures of compounds 16 and 48 supported the design approach and confirmed the key interactions with RORγ protein; the hydrogen bonding with His479 was key to the significant improvement in inverse agonist effect. The results have shown this is a class of potent and selective RORγ inverse agonists, with demonstrated oral bioavailability in rodents.
Subject(s)
Amides/chemistry , Amides/pharmacology , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Drug Inverse Agonism , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors , Amides/pharmacokinetics , Animals , Biphenyl Compounds/pharmacokinetics , Cell Line , Cytokines/immunology , Drug Discovery , Humans , Hydrogen Bonding , Interleukin-17/immunology , Mice , Molecular Docking Simulation , Nuclear Receptor Subfamily 1, Group F, Member 3/immunology , RatsABSTRACT
Osteoarthritis (OA) is a nonsystemic disease for which no oral or parenteral disease-modifying osteoarthritic drug (DMOAD) is currently available. Matrix metalloproteinase 13 (MMP-13) has attracted attention as a target with disease-modifying potential because of its major role in tissue destruction associated with OA. Being localized to one or a few joints, OA is amenable to intra-articular (IA) therapy, which has distinct advantages over oral therapies in terms of increasing therapeutic index, by maximizing drug delivery to cartilage and minimizing systemic exposure. Here we report on the synthesis and biological evaluation of a non-zinc binding MMP-13 selective inhibitor, 4-methyl-1-(S)-({5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)carbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid (1), that is uniquely suited as a potential IA-DMOAD: it has long durability in the joint, penetrates cartilage effectively, exhibits nearly no detectable systemic exposure, and has remarkable efficacy.
Subject(s)
Antirheumatic Agents/chemical synthesis , Benzoxazines/chemical synthesis , Indans/chemical synthesis , Matrix Metalloproteinase Inhibitors , Osteoarthritis/drug therapy , Animals , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/pharmacology , Benzoxazines/pharmacokinetics , Benzoxazines/pharmacology , Cartilage, Articular/metabolism , Cattle , In Vitro Techniques , Indans/pharmacokinetics , Indans/pharmacology , Injections, Intra-Articular , Male , Permeability , Rats , Rats, Sprague-Dawley , Solubility , StereoisomerismABSTRACT
Starting from literature examples of nonsteroidal anti-inflammatory drugs (NSAIDs)-type carboxylic acid γ-secretase modulators (GSMs) and using a scaffold design approach, we identified 4-aminomethylphenylacetic acid 4 with a desirable γ-secretase modulation profile. Scaffold optimization led to the discovery of a novel chemical series, represented by 6b, having improved brain penetration. Further SAR studies provided analog 6q that exhibited a good pharmacological profile. Oral administration of 6q significantly reduced brain Aß42 levels in mice and rats.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Enzyme Inhibitors/chemistry , Phenylacetates/chemistry , Piperidines/chemistry , Administration, Oral , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Brain/metabolism , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Mice , Peptide Fragments/metabolism , Phenylacetates/chemical synthesis , Phenylacetates/pharmacokinetics , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , RatsABSTRACT
A novel class of pyrazolopyrimidine-sulfonamides was discovered as selective dual inhibitors of aurora kinase A (AKA) and cyclin-dependent kinase 1 (CDK1). These inhibitors were originally designed based on an early lead (compound I). SAR development has led to the discovery of potent inhibitors with single digit nM IC(50)s towards both AKA and CDK1. An exemplary compound 1a has demonstrated good efficacy in an HCT116 colon cancer xenograft model.
Subject(s)
Antineoplastic Agents/pharmacology , CDC2 Protein Kinase/antagonists & inhibitors , Colonic Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , Sulfonamides/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aurora Kinase A , Aurora Kinases , CDC2 Protein Kinase/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Colonic Neoplasms/pathology , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Xenograft Model Antitumor AssaysABSTRACT
We have investigated a novel series of acid-derived γ-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which lowered Aß42, increased Aß38, but had little to no effect on Aß40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain Aß42 levels in CF-1 mice and Fischer rats, as well as plasma Aß42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.
ABSTRACT
OBJECTIVE: Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity. METHODS: Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)-induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors. RESULTS: A number of non-hydroxamic acid-containing compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompetitive inhibition, and Dixon plot analysis from competition studies with a zinc chelator (acetoxyhydroxamic acid) and ALS 1-0635 demonstrated nonexclusive binding. ALS 1-0635 inhibited bovine articular cartilage degradation in a dose-dependent manner (48.7% and 87.1% at 500 nM and 5,000 nM, respectively) and was effective in inhibiting interleukin-1alpha- and oncostatin M-induced C1,C2 release in human OA cartilage cultures. ALS 1-0635 modulated cartilage damage in the rat MIA model (mean +/- SEM damage score 1.3 +/- 0.3, versus 2.2 +/- 0.4 in vehicle-treated animals). Most significantly, when treated twice daily with oral ALS 1-0635, rats with surgically induced medial meniscus tear exhibited histologic evidence of chondroprotection and reduced cartilage degeneration, without observable musculoskeletal toxicity. CONCLUSION: The compounds investigated in this study represent a novel class of MMP-13 inhibitors. They are mechanistically distinct from previously reported broad-spectrum MMP inhibitors and do not exhibit the problems previously associated with these inhibitors, including selectivity, poor pharmacokinetics, and MSS liability. MMP-13 inhibitors exert chondroprotective effects and can potentially modulate joint pain, and are, therefore, uniquely suited as potential disease-modifying osteoarthritis drugs.
Subject(s)
Enzyme Inhibitors/therapeutic use , Matrix Metalloproteinase Inhibitors , Musculoskeletal System/pathology , Osteoarthritis/drug therapy , Animals , Cartilage, Articular/drug effects , Cartilage, Articular/pathology , Cartilage, Articular/surgery , Cattle , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Humans , Interleukin-1alpha/pharmacology , Iodoacetates/pharmacology , Iodoacetates/therapeutic use , Iodoacetic Acid/adverse effects , Male , Musculoskeletal System/drug effects , Oncostatin M/pharmacology , Osteoarthritis/chemically induced , Osteoarthritis/pathology , Rats , Rats, Sprague-Dawley , Treatment OutcomeABSTRACT
A series of potent and orally bioavailable 3,4-diaminocyclobutenediones with various amide modifications and substitution on the left side phenyl ring were prepared and found to show significant inhibitory activities towards both CXCR2 and CXCR1 receptors.
Subject(s)
Amides/chemistry , Cyclobutanes/chemical synthesis , Diamines/chemical synthesis , Phenol/chemistry , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Animals , Area Under Curve , Chemistry, Pharmaceutical/methods , Cyclobutanes/pharmacology , Diamines/pharmacology , Drug Design , Humans , Inflammation , Kinetics , Models, Chemical , Rats , Structure-Activity RelationshipABSTRACT
A series of potent and selective 3,4-diamino-1,2,5-thiadiazoles were prepared and found to show excellent binding affinities towards CXCR2 receptor.
Subject(s)
Diamines/chemical synthesis , Receptors, Interleukin-8B/antagonists & inhibitors , Thiadiazoles/chemical synthesis , Diamines/pharmacology , Humans , Protein Binding , Receptors, Interleukin-8B/metabolism , Structure-Activity Relationship , Thiadiazoles/pharmacologyABSTRACT
A series of potent and orally bioavailable 3,4-diaminocyclobutenediones with various fluoroalkyl groups as alpha side chain were prepared and found to show significant improvements in the binding affinities towards both CXCR2 and CXCR1 receptors.
Subject(s)
Cyclobutanes/chemical synthesis , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Animals , Binding Sites , Cyclobutanes/administration & dosage , Cyclobutanes/metabolism , Protein Binding , Rats , Receptors, Interleukin-8A/metabolism , Receptors, Interleukin-8B/metabolismABSTRACT
The mode of binding and the activity of the first two non-zinc chelating, potent, and selective inhibitors of human neutrophil collagenase are reported. The crystal structures of the catalytic domain of MMP-8, respectively complexed with each inhibitor, reveals that both ligands are deeply inserted into the primary specificity subsite S(1)', where they induce a similar conformational change of the surrounding loop that is endowed with the main specificity determinants of MMPs. Accord to this rearrangement, both inhibitors remove the floor of the pocket formed by the Y227 side-chain, rendering available an extra binding region never explored before. The present data show that potent and more selective inhibitors can be obtained by developing ligands able to interact with the selectivity regions of the enzyme rather than with the catalytic zinc ion, which is the common feature of all MMP members.
Subject(s)
Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemistry , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Humans , Ligands , Matrix Metalloproteinase 8/chemistry , Protein Binding , Protein Conformation , Structure-Activity Relationship , Substrate SpecificityABSTRACT
A series of 3,4- and 3,5-disubstituted phenyl-containing cyclobutenedione analogues were synthesized and evaluated as CXCR2 receptor antagonists. Variations in the disubstitution pattern of the phenyl ring afforded new compounds with potent CXCR2 binding affinity in the low nanomolar ranges. Moreover, two potent compounds 19 and 26 exhibited good oral pharmacokinetic profiles.
Subject(s)
Cyclobutanes/chemical synthesis , Cyclobutanes/pharmacology , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Cyclobutanes/chemistry , Haplorhini , Molecular Structure , Protein Binding , Rats , Structure-Activity RelationshipABSTRACT
Comprehensive SAR studies were undertaken in the 3,4-diaminocyclobut-3-ene-1,2-dione class of CXCR2/CXCR1 receptor antagonists to explore the role of the heterocycle on chemokine receptor binding affinities, functional activity, as well as oral exposure in rat. The nature of the heterocycle as well as the requisite substitution pattern around the heterocycle was shown to have a dramatic effect on the overall biological profile of this class of compounds. The furyl class, particularly the 4-halo adducts, was found to possess superior binding affinities for both the CXCR2 and CXCR1 receptors, functional activity, as well as oral exposure in rat versus other heterocyclic derivatives.
Subject(s)
Cyclobutanes/chemistry , Cyclobutanes/pharmacology , Diamines/chemistry , Diamines/pharmacology , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Animals , Cell Line , Cyclobutanes/chemical synthesis , Diamines/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Mice , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of novel and potent 3,4-diamino-2,5-thiadiazole-1-oxides were prepared and found to show excellent binding affinities for CXCR2 and CXCR1 receptors and excellent inhibitory activity of Gro-alpha and IL-8 mediated in vitro hPMN MPO release of CXCR2 and CXCR1 expressing cell lines. On the other hand, a closely related 3,4-diamino-2,5-thiadiazole-dioxide did not show functional activity despite its excellent binding affinities for CXCR2 and CXCR1 in membrane binding assays. A detailed SAR has been discussed in these two closely related structures.
Subject(s)
Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Animals , Chemokine CXCL1/chemistry , Chemokine CXCL1/pharmacology , Chemotactic Factors/chemistry , Chemotactic Factors/pharmacology , Humans , Interleukin-8/chemistry , Interleukin-8/pharmacology , Kinetics , Neutrophils/drug effects , Neutrophils/enzymology , Oxides/chemical synthesis , Oxides/chemistry , Oxides/pharmacokinetics , Oxides/pharmacology , Peroxidase/metabolism , Rats , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistry , Thiadiazoles/pharmacokinetics , Thiadiazoles/pharmacologyABSTRACT
A novel series of cyclobutenedione centered C(4)-alkyl substituted furanyl analogs was developed as potent CXCR2 and CXCR1 antagonists. Compound 16 exhibits potent inhibitory activities against IL-8 binding to the receptors (CXCR2 Ki=1 nM, IC(50)=1.3 nM; CXCR1 Ki=3 nM, IC(50)=7.3 nM), and demonstrates potent inhibition against both Gro-alpha and IL-8 induced hPMN migration (chemotaxis: CXCR2 IC(50)=0.5 nM, CXCR1 IC(50)=37 nM). In addition, 16 has shown good oral pharmacokinetic profiles in rat, mouse, monkey, and dog.
Subject(s)
Chemistry, Pharmaceutical/methods , Furans/chemistry , Furans/pharmacokinetics , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Animals , Area Under Curve , Dogs , Drug Design , Furans/chemical synthesis , Humans , Inhibitory Concentration 50 , Interleukin-8/chemistry , Kinetics , Mice , RatsABSTRACT
Structure-activity studies on lead cyclobutenedione 3 led to the discovery of 4 (SCH 527123), a potent, orally bioavailable CXCR2/CXCR1 receptor antagonist with excellent cell-based activity. Compound 4 displayed good oral bioavailability in rat and may be a potential therapeutic agent for the treatment of various inflammatory diseases.
Subject(s)
Benzamides/pharmacology , Cyclobutanes/pharmacology , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Animals , Benzamides/administration & dosage , Benzamides/chemical synthesis , Biological Availability , Cyclobutanes/administration & dosage , Cyclobutanes/chemical synthesis , Molecular Structure , Rats , Receptors, Interleukin-8A/metabolism , Receptors, Interleukin-8B/metabolism , Structure-Activity RelationshipABSTRACT
A novel series of 3,4-diaminocyclobut-3-ene-1,2-diones was prepared and found to show potent inhibitory activity of CXCR2 binding and IL-8-mediated chemotaxis of a CXCR2-expressing cell line. Microsome stability and Caco2 studies were subsequently used to show that compounds of this chemotype are predicted to have good oral bioavailability and are thus suitable for pharmaceutical development.