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A molecular-modeling study using x-ray analysis of the didemnins indicated the three structural features crucial for biological activity. The structural features were the side chain attached to the amino group of threonine, the isostatine hydroxyl group, and the tyrosine side chain. The synthesis of macrocycle was accomplished through reductive amination using sodium triacetoxyborohydride, stereoselective reduction of the beta-keto ester, and the in situ deprotection of the amino group.

Synthesis of didemnin B analogs that contain the modified L-lactyl-L-propyl portion of the side chain helps analyze structure-activity relationships in this region and the factors responsible for bioactivities of this natural product. Use of a Dess-Martin periodinane reagent and a coupling reagent helps produce gram quantities of the didemnin B macrocycle. Threonine, N-methyl-D-leucine and proline influence the bioactivity of this compound.

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.)

A novel, one-step method for the synthesis of tri- and tetrasubstituted pyrimidin-4-ones is reported. This method involves a titanium(IV)-mediated cyclization involving two sequential condensations of primary and beta-ketoamides. The reaction is operationally facile, readily scalable, and offers rapid entry into differentially substituted pyrimidin-4-one scaffolds. The high functional group compatibility allows for substantial diversification in the products generated from this transformation.