Discovery of the c-Jun N-Terminal Kinase Inhibitor CC-90001.

As a result of emerging biological data suggesting that within the c-Jun N-terminal kinase (JNK) family, JNK1 and not JNK2 or JNK3 may be primarily responsible for fibrosis pathology, we sought to identify JNK inhibitors with an increased JNK1 bias relative to our previous clinical compound tanzisertib (CC-930). This manuscript reports the synthesis and structure-activity relationship (SAR) studies for a novel series of JNK inhibitors demonstrating an increased JNK1 bias. SAR optimization on a series of 2,4-dialkylamino-pyrimidine-5-carboxamides resulted in the identification of compounds possessing low nanomolar JNK inhibitory potency, overall kinome selectivity, and the ability to inhibit cellular phosphorylation of the direct JNK substrate c-Jun. Optimization of physicochemical properties in this series resulted in compounds that demonstrated excellent systemic exposure following oral dosing, enabling in vivo efficacy studies and the selection of a candidate for clinical development, CC-90001, which is currently in clinical trials (Phase II) in patients with idiopathic pulmonary fibrosis (NCT03142191).

Application of 1D and 2D 1H-NMR in the structural elucidation of a N-glucuronidated metabolite and oxidized metabolites generated in microsomal incubation.

Metabolite identification can provide tremendous value in identifying metabolic soft-spots on molecules of interest and to evaluate the potential for generating reactive species. This information is useful in designing stable analogs with acceptable drug-like properties. Two key compounds were found to generate major metabolites that could not be elucidated by mass spectrometry. Nuclear Magnetic Resonance (NMR) is a non-destructive method to obtain structural information. It requires milligram quantities of putative metabolites, typically unavailable in early stage discovery projects. Herein, we demonstrated the application of NMR using microgram quantities of samples to identify the structures of the major metabolites of two discovery compounds. In the first case, we studied structural elucidation of a Nglucuronide on a pyrazole moiety using 1H-NMR due to the instability of the glucuronidated metabolite under mass spectrometric conditions. In the second example, we characterized two oxidized metabolites having identical mass fragmentation using 2D-NMR. In both cases, chemists incorporated these findings into designing analogs to improve metabolic stability.

Screening of 5-HT1A receptor antagonists using molecularly imprinted polymers.

Molecular imprinting produces network polymers with recognition sites for imprint molecules. The high binding affinity and selectivity in conjunction with the polymers' physical robustness positions molecular imprinted polymers (MIPs) as candidates for use as preliminary screens in drug discovery. As such, MIPs can serve as crude mimics of native receptors. In an effort to evaluate the relationship between MIPs and native receptors, imprinted polymers for WAY-100635, an antagonist of the serotonin (5-HT) receptor subtype 5-HT1A were prepared. The resulting MIP P(WAY) was evaluated as an affinity matrix in the screening of serotonin receptor antagonists with known affinities for the native receptor. Rough correlations in affinity between the synthetic P(WAY) and native receptor 5-HT1A were found. These findings provide some support for the analogy between MIPs and native receptors and their possible use as surrogates.