Reza Shiroodi, Timothy J. Montavon, Brandon M. Nelson, John T. Randolph, Daniel E. O’Flynn, Leo Iu, Charles W. Hutchins, Tomas Baikstis, Javier Izquierdo, D. M. Smyth, Navasona Krishnan, Mohammad Mehdi Maneshi, Jordan W. Brown, Gustavo A. Afanador, Rinku Jain, Sarathy Karunan Partha, Lance Bigelow, Boguslaw Nocek, Lukas Talaga, Sujatha M. Gopalakrishnan, Anand Balakrishnan, Mike M. Sheehan, Victoria A. Kurschner, Purvi C. Jejurkar, Omprakash Nacham, Dongjian Hu, Anna Yarilina, Noah P. Bradley, Alex M. Chapman, Ashish Thakur, Sanjay C. Panchal, Mihiro Sunose, Ioanna Zoi, Michael J. Dart, J. Brad Shotwell, Madhurima Benekareddy, Renee N. Sadowski, Andrew M. Swensen
Abstract Herein, we report the discovery and optimization of a series of cluster of differentiation 38 (CD38) inhibitors derived from a virtual ligand screening (VLS) campaign. VLS identified imidazopyridazine hit 9, which was optimized to a novel and potent CD38 inhibitor peripheral tool 25 (A-8531) with an excellent pharmacokinetic profile. A cocrystal structure in addition to biophysical and biochemical characterization of 25 is consistent with uncompetitive inhibition of CD38 via the formation of covalent adduct 28. Further structure- and property-based modifications of 25 afforded sulfuryl pyrazole 39 (A-3190) with improved CNS distribution properties. Brain-penetrant thienopyrimidine 39 shows robust rodent pharmacokinetics and in vivo target engagement across skin, lung, liver, and brain, making it an excellent CD38 tool for the study of indications requiring engagement of CD38 in the brain.