This invention relates to novel carboxycycloalkylamino derivatives. The carboxycycloalkylamino derivatives of the present invention are modulators of the sphingosine-1-phosphate (S1P) receptors and have a number of therapeutic applications, particularly in the treatment of hyperproliferative and autoimmune diseases, in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
The S1P receptors 1-5 constitute a family of seven-transmembrane G-protein coupled receptors. These receptors, referred to as S1P1 to S1P5, are activated via binding by sphingosine-1-phosphate, which is produced by the sphingosine kinase phosphorylation of sphingosine. S1P receptors are cell surface receptors involved in a variety of cellular processes, including cell proliferation and differentiation, cell survival, and cell migration. S1P is found in plasma and a variety of other tissues and exerts autocrine and paracrine effects.
Recent studies indicate that S1P binds to the S1P1 receptor to promote tumor angiogenesis by supporting the migration, proliferation and survival of endothelial cells (ECs) as they form new vessels within tumors (tumor angiogenesis) (Lee et al., Cell. 99:301-312 (1999) Paik et al., J. Biol. Chem. 276:11830-11837 (2001)). Because S1P is required for optimal activity of multiple proangiogenic factors, modulating S1P1 activation may affect angiogenesis, proliferation, and interfere with tumor neovascularization, vessel maintenance and vascular permeability.
Other diseases or conditions that may be treated with the compounds of the present invention include organ transplant rejection and inflammatory diseases, which are believed to proceed via modulating the S1P receptors.
Thus, the identification of compounds which modulate the activity of the S1P1 receptor to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is therefore desirable.