A partially open conformation of an androgen receptor ligand-binding domain with drug-resistance mutations.

Mutations in the androgen receptor (AR) ligand-binding domain (LBD) can cause resistance to drugs used to treat prostate cancer. Commonly found mutations include L702H, W742C, H875Y, F877L and T878A, while the F877L mutation can convert second-generation antagonists such as enzalutamide and apalutamide into agonists. However, pruxelutamide, another second-generation AR antagonist, has no agonist activity with the F877L and F877L/T878A mutants and instead maintains its inhibitory activity against them.

Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV-1 Activities and Improved Oral Bioavailability.

Blocking the entry of an HIV-1 targeting CCR5 coreceptor has emerged as an attractive strategy to develop HIV therapeutics. Maraviroc is the only CCR5 antagonist approved by FDA; however, serious side effects limited its clinical use. Herein, 21 novel tropane derivatives () were designed and synthesized based on the CCR5-maraviroc complex structure.

Structure-Based Design of 1-Heteroaryl-1,3-propanediamine Derivatives as a Novel Series of CC-Chemokine Receptor 5 Antagonists.

CC-chemokine receptor 5 (CCR5) is an attractive target for preventing the entry of human immunodeficiency virus 1 (HIV-1) into human host cells. Maraviroc is the only CCR5 antagonist, and it was marketed in 2007. To overcome the shortcomings of maraviroc, structure-based drug design was performed to minimize CYP450 inhibition and to enhance anti-HIV potency and bioavailability.

Rhodium(III)-Catalyzed Site-Selective C-H Alkylation and Arylation of Pyridones Using Organoboron Reagents.

In this study we developed a method for the pyridine-directed, rhodium-catalyzed, site-selective C-H alkylation and arylation of pyridones using commercially available trifluoroborate reagents. This simple and versatile transformation proceeded smoothly under relatively mild conditions with perfect site selectivity. The coupling groups in the boron reagents can be extended to primary alkyl, benzyl, and cycloalkyl.