Synta Pharmaceuticals Corporation

Madrigal Pharmaceuticals, Inc.

Rongzhen Lu

Yumiko Wada

James G Barsoum

Albert Y Hsia

The present invention is directed to compositions and methods for modulating c-Rel-dependent cytokine production without materially altering the level of expression of NF&#x3ba;B and/or the amount of I&#x3ba;B. The present invention is also directed to screening for modulators of c-Rel activity as determined by assaying for altered subcellular localization of c-Rel but where the level of expression of NF&#x3ba;B and/or the amount of I&#x3ba;B is materially unaltered.

Compositions and methods for modulating c-Rel-dependent cytokine production

This invention features pyrimidine compounds of formula (I):  aryl, or heteroaryl; each of Rand R, independently, is R, halogen, nitro, cyano, isothionitro, SR, or OR; or Rand R, taken together, is carbonyl; Ris R, alkenyl, alkynyl, OR, OC(O)R, SOR, S(O)R, S(O)NRR, SR, NRR, NRCOR, NRC(O)OR, NRC(O)NRR, NRSOR, COR, C(O)OR, or C(O)NRR; Ris H or alkyl; n is 0, 1, 2, 3, 4, 5, or 6; X is O, S, S(O), S(O), or NR; Y is a covalent bond, CH, C(O), C&#x2550;N&#x2014;R, C&#x2550;N&#x2014;OR, C&#x2550;N&#x2014;SR, O, S, S(O), S(O), or NR; Z is N or CH; one of U and V is N, and the other is CR; and W is O, S, S(O), S(O), NR, or NC(O)R; in which each of Rand R, independently, is H, alkyl, aryl, heteroaryl; and each of Rand R, independently, is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl. The featured compounds inhibit the production of IL-12, IL-23 and IL-27 and are useful for treating disorders associated with IL-12, IL-23 and IL-27 overproduction or misregulation, such as inflammatory and immune disorders.

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Lincoln, MA, United States of America

Rongzhen Lu