Discovery of N-[2-[2-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-5-oxazolyl]phenyl]-N-methyl-4- morpholineacetamide as a Novel and Potent Inhibitor of Inosine Monophosphate Dehydrogenase with Excellent in Vivo Activity

• Published in: Journal of medicinal chemistry Vol. 45; no. 11; pp. 2127 - 2130
• Main Authors: Dhar, T. G. Murali, Shen, Zhongqi, Guo, Junqing, Liu, Chunjian, Watterson, Scott H, Gu, Henry H, Pitts, William J, Fleener, Catherine A, Rouleau, Katherine A, Sherbina, N. Z, McIntyre, Kim W, Witmer, Mark R, Tredup, Jeffrey A, Chen, Bang-Chi, Zhao, Rulin, Bednarz, Mark S, Cheney, Daniel L, MacMaster, John F, Miller, Laura M, Berry, Karen K, Harper, Timothy W, Barrish, Joel C, Hollenbaugh, Diane L, Iwanowicz, Edwin J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.05.2002; Amer Chemical Soc
• Subjects: Animals; Antibody Formation - drug effects; Arthritis, Experimental - drug therapy; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Chemistry, Medicinal; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay; Immunomodulators; IMP Dehydrogenase - antagonists & inhibitors; Life Sciences & Biomedicine; Male; Medical sciences; Mice; Mice, Inbred BALB C; Morpholines - chemical synthesis; Morpholines - chemistry; Morpholines - pharmacology; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - pharmacology; Oxazoles - chemical synthesis; Oxazoles - chemistry; Oxazoles - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Rats, Inbred Lew; Science & Technology; Structure-Activity Relationship; IMP DEHYDROGENASE; ACTIVATION; MECHANISM; MYCOPHENOLIC-ACID; 5'-MONOPHOSPHATE DEHYDROGENASE; CDNAS; Rat; Diseases of the osteoarticular system; Inflammatory joint disease; Morpholine derivatives; Structure activity relation; Chemical synthesis; Oxazole derivatives; Oxygen nitrogen heterocycle; Immunopathology; Enzyme; Rodentia; IMP dehydrogenase; Oral administration; Enzyme inhibitor; In vitro; Immunomodulator; In vivo; Vertebrata; Experimental disease; Mammalia; Treatment; Mouse; Animal; Rheumatoid arthritis; Carboxamide; Benzenic compound; Oxidoreductases
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0105777

Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme that is involved in the de novo synthesis of purine nucleotides. Novel 2-aminooxazoles were synthesized and tested for inhibition of IMPDH catalytic activity. Multiple analogues based on this chemotype were found to inhibit IMPDH with low nanomolar potency. One of the analogues (compound 23) showed excellent in vivo activity in the inhibition of antibody production in mice and in the adjuvant induced arthritis model in rats.