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

ACS Med Chem Lett. 2019 Jun 27;10(8):1134-1139. doi: 10.1021/acsmedchemlett.9b00134.

Philip N Collier ¹, Heather C Twin ² ¹, Ronald M A Knegtel ² ¹, Dean Boyall ² ¹, Guy Brenchley ² ¹, Christopher J Davis ² ¹, Shazia Keily ² ¹, Chau Mak ² ¹, Andrew Miller ² ¹, Françoise Pierard ² ¹, Luca Settimo ² ¹, Clare M Bolton ² ¹, Peter Chiu ² ¹, Adam Curnock ² ¹, Elisabeth Doyle ¹, Adam J Tanner ² ¹, Juan-Miguel Jimenez ² ¹

Affiliations

1 Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
2 Vertex Pharmaceuticals (Europe) Ltd., 86-88 Jubilee Avenue, Milton Park, Abingdon OX14 4RW, United Kingdom.

PMID: 31417666 DOI: 10.1021/acsmedchemlett.9b00134

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-126328

PKC-theta inhibitor 1

99.73%, PKCθ Inhibitor

PKC

Inflammation/Immunology

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