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

Abstract

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.

• Authors: Philip N Collier, Heather C Twin, Ronald M A Knegtel, Dean Boyall, Guy Brenchley, Christopher J Davis, Shazia Keily, Chau Mak, Andrew Miller, Françoise Pierard, Luca Settimo, Clare M Bolton, Peter Chiu, Adam Curnock, Elisabeth Doyle, Adam J Tanner, Juan-Miguel Jimenez
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 10 Issue 8 Pg. 1134-1139 (Aug 08 2019) ISSN: 1948-5875 [Print] United States
• PMID: 31417666 (Publication Type: Journal Article)