Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors

Christopher A Luckhurst; Perla Breccia; Andrew J Stott; Omar Aziz; Helen L Birch; Roland W Bürli; Samantha J Hughes; Rebecca E Jarvis; Marieke Lamers; Philip M Leonard; Kim L Matthews; George McAllister; Scott Pollack; Elizabeth Saville-Stones; Grant Wishart; Dawn Yates; Celia Dominguez

doi:10.1021/acsmedchemlett.5b00302

Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors

ACS Med Chem Lett. 2015 Dec 10;7(1):34-9. doi: 10.1021/acsmedchemlett.5b00302. eCollection 2016 Jan 14.

Authors

Christopher A Luckhurst¹, Perla Breccia¹, Andrew J Stott¹, Omar Aziz¹, Helen L Birch¹, Roland W Bürli¹, Samantha J Hughes¹, Rebecca E Jarvis¹, Marieke Lamers¹, Philip M Leonard¹, Kim L Matthews¹, George McAllister¹, Scott Pollack¹, Elizabeth Saville-Stones¹, Grant Wishart¹, Dawn Yates¹, Celia Dominguez²

Affiliations

¹ BioFocus, Charles River , Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, United Kingdom.
² CHDI Management/CHDI Foundation Inc. , 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States.

Abstract

Potent and selective class IIa HDAC tetrasubstituted cyclopropane hydroxamic acid inhibitors were identified with high oral bioavailability that exhibited good brain and muscle exposure. Compound 14 displayed suitable properties for assessment of the impact of class IIa HDAC catalytic site inhibition in preclinical disease models.

Keywords: CNS exposure; Class IIa HDAC inhibitors; Huntington’s disease; cyclopropanation; hydroxamic acid; tetrasubstituted cyclopropane.