title: Optimization of a potent class of arylamide colony-stimulating factor-1 receptor inhibitors leading to anti-inflammatory clinical candidate 4-cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino)acetyl]-4-piperidinyl]phenyl]-1H-imidazole-2-carboxamide (JNJ-28312141).
abstract: A class of potent inhibitors of colony-stimulating factor-1 receptor (CSF-1R or FMS), as exemplified by 8 and 21, was optimized to improve pharmacokinetic and pharmacodynamic properties and potential toxicological liabilities. Early stage absorption, distribution, metabolism, and excretion assays were employed to ensure the incorporation of druglike properties resulting in the selection of several compounds with good activity in a pharmacodynamic screening assay in mice. Further investigation, utilizing the type II collagen-induced arthritis model in mice, culminated in the selection of anti-inflammatory development candidate JNJ-28312141 (23, FMS IC(50) = 0.69 nM, cell assay IC(50) = 2.6 nM). Compound 23 also demonstrated efficacy in rat adjuvant and streptococcal cell wall-induced models of arthritis and has entered phase I clinical trials.
authors: Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, Pennsylvania 19477, United States. cillig@its.jnj.com
authors: Carl R
authors: CR
authors: Illig
authors: Carl L
authors: CL
authors: Manthey
authors: Mark J
authors: MJ
authors: Wall
authors: Sanath K
authors: SK
authors: Meegalla
authors: Jinsheng
authors: J
authors: Chen
authors: Kenneth J
authors: KJ
authors: Wilson
authors: Shelley K
authors: SK
authors: Ballentine
authors: Renee L
authors: RL
authors: Desjarlais
authors: Carsten
authors: C
authors: Schubert
authors: Carl S
authors: CS
authors: Crysler
authors: Yanmin
authors: Y
authors: Chen
authors: Christopher J
authors: CJ
authors: Molloy
authors: Margery A
authors: MA
authors: Chaikin
authors: Robert R
authors: RR
authors: Donatelli
authors: Edward
authors: E
authors: Yurkow
authors: Zhao
authors: Z
authors: Zhou
authors: Mark R
authors: MR
authors: Player
authors: Bruce E
authors: BE
authors: Tomczuk
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D011917:Rats, Inbred Lew; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C549569:4-cyano-N-(2-(1-cyclohexen-1-yl)-4-(1-((dimethylamino)acetyl)-4-piperidinyl)phenyl)-1H-imidazole-2-carboxamide; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D010880:Piperidines; D016186:Receptor, Macrophage Colony-Stimulating Factor