Profiling of dihydroorotate dehydrogenase, p38 and JAK inhibitors in the rat adjuvant-induced arthritis model: a translational study.
OBJECTIVE
Translational animal models are essential in the prediction of the efficacy and side effects of new chemical entities. We have carried out a thorough study of three distinct disease-modifying antirheumatic drugs (DMARDs) in an adjuvant-induced arthritis (AIA) model in the rat and critically appraised the results in the context of the reported clinical experience in rheumatoid arthritis (RA) patients.


METHODS
Teriflunomide - a dihydroorotate dehydrogenase (DHODH) inhibitor; AL8697 - a selective p38 MAPK inhibitor; and tofacitinib - a Janus kinase (JAK) inhibitor; were selected as representatives of their class and dose-response studies carried out using a therapeutic 10-day administration scheme in arthritic rats. Paw swelling and body weight were periodically monitored, and joint radiology and histology, lymph organ weight and haematological and biochemical parameters evaluated at study completion.


RESULTS
All three drugs demonstrated beneficial effects on paw swelling, bone lesions and splenomegalia, with p38 inhibition providing the best anti-inflammatory effect and JAK inhibition the best DMARD effect. Leukopenia, body weight loss and gastrointestinal toxicity were dose-dependently observed with teriflunomide treatment. p38 MAPK inhibition induced leukocytosis and increased total plasma cholesterol. JAK inhibition, normalized platelet, reticulocyte and neutrophil counts, and alanine aminotransferase (ALT) levels while inducing lymphopenia and cholesterolemia.


CONCLUSIONS
This multiparametric approach can reveal specific drug properties and provide translational information. Whereas the complex profile for p38 inhibition in AIA is not observed in human RA, immunosuppressants such as DHODH and JAK inhibitors show DMARD properties and side effects seen in both AIA and RA.
Drug Discovery, Almirall, Sant Feliu de Llobregat, Barcelona, Spain. cristina.balague@almirall.com
C
C
Balagué
M
M
Pont
N
N
Prats
N
N
Godessart
D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D003437:Crotonates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000090722:Dihydroorotate Dehydrogenase; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000209:etiology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D041981:Gastrointestinal Tract / Q000187:drug effects; D006207:Half-Life; D006885:Hydroxybutyrates; D006937:Hypercholesterolemia / Q000139:chemically induced; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D007596:Joints / Q000187:drug effects / Q000276:immunology; D007960:Leukocyte Disorders / Q000139:chemically induced; D008297:Male; D009570:Nitriles; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D010880:Piperidines; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013163:Splenomegaly / Q000209:etiology / Q000517:prevention & control; D014052:Toluidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D015431:Weight Loss / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
C575439:3-(3-tert-butyl-6,8-difluoro(1,2,4)triazolo(4,3-a)pyridin-7-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide; D018501:Antirheumatic Agents; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003437:Crotonates; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents; D009570:Nitriles; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D014052:Toluidines; C527525:teriflunomide; C479163:tofacitinib; D044925:Oxidoreductases Acting on CH-CH Group Donors; D053612:Janus Kinases; D048051:p38 Mitogen-Activated Protein Kinases