Open AccessDiscovery of Selective, Orally Bioavailable Pyrazolopyridine Inhibitors of Protein Kinase Cθ (PKCθ) That Ameliorate Symptoms of Experimental Autoimmune Encephalomyelitis
Author(s) -
Philip N. Collier,
Heather Twin,
Ronald M.A. Knegtel,
Dean Boyall,
Guy Brenchley,
Christopher J. Davis,
Shazia B. Keily,
Chau Mak,
Andrew T. Miller,
Françoise Y. T. M. Pierard,
Luca Settimo,
Clare Bolton,
Peter Chiu,
Adam P. Curnock,
Elisabeth G. Doyle,
Adam Tanner,
Juan-Miguel Jiménez
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00134
Subject(s) - protein kinase c , orally active , experimental autoimmune encephalomyelitis , amine gas treating , pharmacology , chemistry , active site , kinase , enzyme , medicine , multiple sclerosis , biochemistry , immunology , oral administration , organic chemistry
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.