Toreforant

{{Short description|Antagonist of the histamine H4 receptor.}}

{{Chembox

| ImageFile = Toreforant.svg

|IUPACName=5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-methyl-N-[3-(1-methylpiperidin-4-yl)propyl]pyrimidin-2-amine

|Section1={{Chembox Identifiers

| CASNo = 952494-46-1

| ChEMBL = 3301609

| DrugBank = DB12522

| ChemSpiderID = 31389942

| KEGG = D10735

| PubChem = 23650961

| UNII = U6LA7G393X

| StdInChI=1S/C23H32N6/c1-15-12-16(2)21-20(13-15)27-22(28-21)19-14-25-23(26-17(19)3)24-9-5-6-18-7-10-29(4)11-8-18/h12-14,18H,5-11H2,1-4H3,(H,27,28)(H,24,25,26)

| StdInChIKey = FCRFVPZAXGJLPW-UHFFFAOYSA-N

| SMILES = CC1=CC(=C2C(=C1)NC(=N2)C3=CN=C(N=C3C)NCCCC4CCN(CC4)C)C

}}

|Section2={{Chembox Properties

|C=23|H=32|N=6

}}

}}

Toreforant (JNJ-38518168) is an orally-dosed selective antagonist of the histamine H₄ receptor that has been studied for various health conditions. It is the successor of a number of H₄-selective compounds developed by Johnson & Johnson.{{cite book | vauthors = Thurmond RL, Venable J, Savall B, La D, Snook S, Dunford PJ, Edwards JP | title = Histamine and Histamine Receptors in Health and Disease | date = 2017 | chapter = Clinical Development of Histamine H4 Receptor Antagonists | series = Handbook of Experimental Pharmacology | volume = 241 | pages = 301–320 | pmid = 28233185 | doi = 10.1007/164_2016_130 | isbn = 978-3-319-58192-7 }} Phase IIa clinical trials completed as recently as November 2018 continue to suggest that toreforant is safe.{{cite journal | vauthors =Kollmeier AP, Barnathan ES, O'Brien C, Chen B, Xia Y, Zhou B, Loza MJ, Silkoff PE, Ge M, Thurmond RL | title = A phase 2a study of toreforant, a histamine H4 receptor antagonist, in eosinophilic asthma | journal = Annals of Allergy, Asthma & Immunology | volume = 121 | issue = 5 | pages = 568–574 | date = 2018 | doi = 10.1016/j.anai.2018.08.001 | pmid = 30102965 | s2cid = 51972933 }}

As of the end of 2020, there is no regulator-approved H₄ antagonist. In U.S. Phase II clinical trials, toreforant, by itself, did not show efficacy against eosinophilic asthma. The drug did show at least partial efficacy against rheumatoid arthritis in patients who were nonresponsive to methotrexate.{{cite journal | vauthors = Thurmond RL , Greenspan A, Radziszewski W, Xu XL, Miao Y, Chen B, Ge T, Zhou B, Baker DG, Pavlova D, Ritchlin CT, Tanaka Y, Takeuchi T, Smolen JS | title = Toreforant, A Histamine H4 Receptor Antagonist, in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy: Results of 2 Phase II Studies | journal = The Journal of Rheumatology | volume = 43 | issue = 9 | pages = 1637–1642 | date = September 2016 | doi = 10.3899/jrheum.160164| pmid = 27422891 | s2cid = 46885520 }} As the H₄ receptor is widely implicated in the regulation of inflammatory states, the potential uses for an H₄ antagonist remain significant.{{cite journal | vauthors = Saravanan C, Bharti SK, Jaggi S, Singh SK | title = Histamine H₄ receptor: a novel target for inflammation therapy | journal = Mini Reviews in Medicinal Chemistry | volume = 11 | issue = 2 | pages = 143–58 | date = February 2011 | pmid = 21222579 | doi = 10.2174/138955711794519519 }}{{cite book | vauthors = Thurmond RL, Venable J, Savall B, La D, Snook S, Dunford PJ, Edwards JP | chapter = Clinical Development of Histamine H4 Receptor Antagonists | title = Histamine and Histamine Receptors in Health and Disease | series = Handbook of Experimental Pharmacology | year = 2017 | volume = 241 | pages = 301–320 | pmid = 28233185 | doi = 10.1007/164_2016_130 | isbn = 978-3-319-58192-7 }}{{cite journal | vauthors = Thangam EB, Jemima EA, Singh H, Baig MS, Khan M, Mathias CB, Church MK, Saluja R | display-authors = 6 | title = The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets | journal = Frontiers in Immunology | year = 2018 | volume = 9 | pages = 1873 | pmid = 30150993 | doi = 10.3389/fimmu.2018.01873 | pmc = 6099187 | doi-access = free }}