| Autor: |
Hao, Junliang, Beck, James P., Schaus, John M., Krushinski, Joseph H., Chen, Qi, Beadle, Christopher D., Vidal, Paloma, Reinhard, Matthew R., Dressman, Bruce A., Massey, Steven M., Boulet, Serge L., Cohen, Michael P., Watson, Brian M., Tupper, David, Gardinier, Kevin M., Myers, Jason, Johansson, Anette M., Richardson, Jeffery, Richards, Daniel S., Hembre, Erik J., Remick, David M., Coates, David A., Bhardwaj, Rajni M., Diseroad, Benjamin A., Bender, David, Stephenson, Greg, Wolfangel, Craig D., Diaz, Nuria, Getman, Brian G., Wang, Xu-shan, Heinz, Beverly A., Cramer, Jeff W., Zhou, Xin, Maren, Deanna L., Falcone, Julie F., Wright, Rebecca A., Mitchell, Stephen N., Carter, Guy, Yang, Charles R., Bruns, Robert F., Svensson, Kjell A. |
| Zdroj: |
Journal of Medicinal Chemistry; October 2019, Vol. 62 Issue: 19 p8711-8732, 22p |
| Abstrakt: |
Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia. |
| Databáze: |
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