Overcoming the Pregnane X Receptor Liability: Rational Design to Eliminate PXR-Mediated CYP Induction.
| Autor: | Ramanjulu JM; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Williams SP; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Lakdawala AS; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., DeMartino MP; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Lan Y; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Marquis RW; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States. |
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| Jazyk: | angličtina |
| Zdroj: | ACS medicinal chemistry letters [ACS Med Chem Lett] 2021 Aug 10; Vol. 12 (9), pp. 1396-1404. Date of Electronic Publication: 2021 Aug 10 (Print Publication: 2021). |
| DOI: | 10.1021/acsmedchemlett.1c00187 |
| Abstrakt: | The pregnane X receptor (PXR) regulates expression of proteins responsible for all three phases required for the detoxification mechanism, which include CYP450 enzymes, phase II enzymes, and multidrug efflux pumps. Therefore, PXR is a prominent receptor that is responsible for xenobiotic excretion and drug-drug interactions. Pyrimidinone 1 is an antagonist of the calcium sensing receptor (CaSR) and a strong activator of PXR. Repeat oral administration revealed diminished exposures over time, which prohibited further progression. A medicinal chemistry campaign was initiated to understand and abolish activation of PXR in order to increase systemic exposures. Rational structure-activity relationship investigations utilizing cocrystal structures and a de novo pharmacophore model resulted in compounds devoid of PXR activation. These studies culminated in the first orally active CaSR antagonist 8 suitable for progression. Cocrystallography, the pharmacophore model employed, and additional observations reported herein supported rational elimination of PXR activation and have applicability across diverse chemical classes to help erase PXR-driven drug-drug interactions. Competing Interests: The authors declare no competing financial interest. (© 2021 American Chemical Society.) |
| Databáze: | MEDLINE |
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