Discovery of Selective, Orally Bioavailable Pyrazolopyridine Inhibitors of Protein Kinase Cθ (PKCθ) That Ameliorate Symptoms of Experimental Autoimmune Encephalomyelitis

• Published in: ACS medicinal chemistry letters Vol. 10; no. 8; pp. 1134 - 1139
• Main Authors: Collier, Philip N, Twin, Heather C, Knegtel, Ronald M. A, Boyall, Dean, Brenchley, Guy, Davis, Christopher J, Keily, Shazia, Mak, Chau, Miller, Andrew, Pierard, Françoise, Settimo, Luca, Bolton, Clare M, Chiu, Peter, Curnock, Adam, Doyle, Elisabeth, Tanner, Adam J, Jimenez, Juan-Miguel
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08.08.2019
• Subjects: Letter; kinases; PKCθ; multiple sclerosis; oxetane
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.9b00134

PKCθ plays an important role in T cell biology and is a validated target for a number of disease states. A series of potent and selective PKCθ inhibitors were designed and synthesized starting from a HTS hit compound. Cell activity, while initially a challenge to achieve, was built into the series by transforming the nitrile unit of the scaffold into a primary amine, the latter predicted to form a new hydrogen bond to Asp508 near the entrance of the ATP binding site of PKCθ. Significant improvements in physiochemical parameters were observed on introduction of an oxetane group proximal to a primary amine leading to compound 22, which demonstrated a reduction of symptoms in a mouse model of multiple sclerosis.