Targeting the p300/CBP Axis in Lethal Prostate Cancer.

Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain.

Two-directional synthesis and biological evaluation of alkaloid 5-epi-cis-275B'.

The first total synthesis of myrmicine ant alkaloid 5-epi-cis-275B' (4) is presented. A tandem cyclisation established the entire core of the structure in a single transformation as well as the required 2,5-anti stereochemistry. Two-directional synthesis was used to furnish the cyclisation precursor 2, as in each of the subsequent steps towards the natural product.

Cycloaddition of chiral tert-butanesulfinimines with trimethylenemethane.

The cycloaddition of chiral tert-butanesulfinimines with trimethylenemethane is found to give facile access to methylene-pyrrolidines with good yields and diastereoselectivities. The full scope of the cycloaddition is explored, and a range of transformations of the formed methylenepyrrolidines to give a range of functionalized chiral pyrrolidines is presented.

In vitro and in vivo SAR of pyrido[3,4-d]pyramid-4-ylamine based mGluR1 antagonists.

The SAR of a series of novel pyrido[3,4-d]pyramid-4-ylamine mGluR1 antagonists is described. The multiple of the unbound K(i) in cerebrospinal fluid necessary to give morphine like analgesic effects in an electromyograph pinch model in rodents is determined and the effect of structure on CNS penetration examined.

Structure-activity relationships of novel non-competitive mGluR1 antagonists: a potential treatment for chronic pain.

A series of novel mGluR1 antagonists have been prepared. Incorporation of fragments derived from weak lead matter into a library led to enhanced potency in a new chemical series. A chemistry driven second library iteration, covering a greatly enhanced area of chemical space, maintained good potency and introduced metabolic stability.