Modulators of glucocorticoid receptor, AP-1, and/or NF-kB activity and use thereof

Abstract

The present invention provides novel non-steroidal compounds which are useful in treating diseases associated with modulation of the glucocorticoid receptor, AP-1, and / or NF-kappaB activity, including inflammatory and immune diseases, having the structure of formula (I): an enantiomer, diastereomer, or tautomer thereof, or a prodrug ester thereof, or a pharmaceutically-acceptable salt thereof, in which: Z is heterocyclo or heteroaryl; A is a 5- to 8-membered carbocyclic ring or a 5- to 8-membered heterocyclic ring; B is a cycloalkyl, cycloalkenyl, aryl, heterocyclo, or heteroaryl ring, wherein each ring is fused to the A ring on adjacent atoms and optionally substituted by one to four groups which are the same or different and are independently selected from R5, R6, R7, and R8; J1, J2, and J3 are at each occurrence the same or different and are independently -A1QA2-; Q is a bond, O, S, S(O), or S(O)2; A1 and A2 are the same or different and are at each occurrence independently selected from a bond, C1-3alkylene, substituted C1-3alkylene, C2-4alkenylene, and substituted C2-4alkenylene, provided that A1 and A2 are chosen so that ring A is a 5- to 8-membered carbocyclic or heterocyclic ring; R1 to R11 are as defined herein. Also the present invention provides pharmaceutical compositions and methods of treating inflammatory- or immune-associated diseases and obesity and diabetes employing said compounds.

Description

[0001] This application claims priority to US Provisional Application 60 / 836496, filed August 9, 2006, the disclosure of which is incorporated herein by reference in its entirety. technical field [0002] The present invention relates to novel non-steroidal compounds which are potent modulators of glucocorticoid receptors and / or AP-1 and / or NF-κB activity and are therefore useful in the treatment of diseases such as inflammatory or immune-related diseases, and to Methods of using these compounds to treat these and related diseases. Background technique [0003] Transcription factors NF-κB and AP-1 are involved in regulating the expression of many genes involved in mediating inflammation and immune response. NF-κB regulates the transcription of genes, including TNF-α, IL-1, IL-2, IL-6, adhesion molecules such as E-selectin, and chemokines such as Rantes. AP-1 regulates cell Production of the hormones TNF-α, IL-1, IL-2, and matrix metalloproteinases. Drug therapy targeting TN...

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Problems solved by technology

However, its systemic use is limited by side effects

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