Pyrido[2,3-d]pyrimidin-5-ones: A Novel Class of Antiinflammatory Macrophage Colony-Stimulating Factor-1 Receptor Inhibitors

Abstract

A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.

RN486, a Selective Bruton's Tyrosine Kinase Inhibitor, Abrogates Immune Hypersensitivity Responses and Arthritis in Rodents

“…It is not clear whether BCR or FcR is involved because B cell and humoral autoimmunity have not been shown to contribute to AIA. Other possible receptors include CSF1R and myeloid DAP12-associating lectin-1, both of which depend on ITAM-containing DAP12 for signaling, and are implicated in immune arthritis in rodents (Huang et al, 2009;Joyce-Shaikh et al, 2010). Although the exact mechanism remains to be defined, our data suggest that Btk inhibitors may also produce efficacy in autoimmune conditions in which T cell and innate immune responses dominate.…”

“…DAP12 functions as an adaptor protein for multiple receptors, including macrophage colony-stimulating factor 1 receptor (CSF1R) and myeloid DAP12-associating lectin-1 receptor. Both receptors have been implicated in the development of immune arthritis (Huang et al, 2009;Joyce-Shaikh et al, 2010). Also importantly, CSF1R, along with FcR gamma chain, provides a secondary, but indispensable, signal for RANKL to promote osteoclast differentiation and, subsequently, bone resorption (Koga et al, 2004).…”

Heterogeneous Catalytic Hydrogenation Reactions in Continuous‐Flow Reactors

“…In the same manner as described for the selected samples above, functional group deprotection via continuous-flow hydrogenation on the H-Cube reactor has been employed in numerous synthetic studies, mainly in the context of drug discovery applications. [12,[107][108][109][110]…”

Difluorotetrahydropyridothiazinone: A Selective β‐Galactosidase Inhibitor

“…Recently, introducing a geminal difluoromethylene group at position‐3 in a piperidine ring attracted notable interest. Compounds owning this feature have been shown to display pronounced activity in anti‐inflammatory macrophage colony‐stimulating factor‐1 receptor inhibition 9 as well as novel histamine‐3 receptor inverse agonists 10, 11.…”