Discovery of 6-(2,4-Difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Pamapimod) and 6-(2,4-Difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (R1487) as Orally Bioavailable and Highly Selective Inhibitors of p38α Mitogen-Activated Protein Kinase

Abstract

The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.

The Novel p38 Inhibitor, Pamapimod, Inhibits Osteoclastogenesis and Counteracts Estrogen-Dependent Bone Loss in Mice

“…Excessive osteoclast activity results in bone‐related disease, including postmenopausal osteoporosis, rheumatoid arthritis (RA), and Paget's disease . Here, we showed PAM, a novel selective p38 MAPK inhibitor, inhibits the formation and resorption of multinucleated osteoclasts.…”

“…(14,15) However, it is still interesting whether p38 inhibitors, particularly selective inhibitors, can be used for the treatment of osteolytic diseases such as osteoporosis. Indeed, a selective p38 inhibitor, pamapimod (PAM), (16) was previously used for the treatment of rheumatoid arthritis. (17) It was proven to be effective for the prevention of joint destruction with the underlying mechanisms needing further clarification.…”

Retinal Degenerative Diseases

“…Although inhibiting p38MAPK to enhance neuritogenesis may be a postnatal photoreceptor-specific phenomenon, it is possible that this is an "off-target" mechanism of the molecule, perhaps due to inhibition of one or more other kinases. Indeed, the kinase selectivity profile of the pyrimidinopyridone family from which this molecule was found demonstrates submicromolar inhibition of 10 out of the 300 kinases tested (Goldstein et al 2011). Future studies performed in a photoreceptor-specific systems pharmacology context may uncover currently unknown effects of similar small molecules on cellular phenotypes.…”

Use of a Machine Learning-Based High Content Analysis Approach to Identify Photoreceptor Neurite Promoting Molecules

“…CHEMBL-1766490 is reported to have p38α MAPK inhibitory activity (Goldstein et al, 2011). It has been reported that p38α inhibition induces neuronal differentiation, whereas other reports suggest that neurite outgrowth is inhibited following p38α knockdown in PC12 and P19 committed neuronal cell lines (Morooka and Nishida, 1998; Iwasaki et al, 1999; Aouadi et al, 2006).…”

“…Although inhibiting p38MAPK to enhance neuritogenesis may be a postnatal photoreceptor-specific phenomenon, it is possible that this is an “off-target” mechanism of the molecule, perhaps due to inhibition of one or more other kinases. Indeed, the kinase selectivity profile of the pyrimidinopyridone family from which this molecule was found demonstrates submicromolar inhibition of 10 out of the 300 kinases tested (Goldstein et al, 2011). Future studies performed in a photoreceptor-specific systems pharmacology context may uncover currently unknown mechanisms of actions of similar small molecules on cellular phenotypes.…”