Discovery of Orally Bioavailable FGFR2/FGFR3 Dual Inhibitors via Structure-Guided Scaffold Repurposing Approach.

Fibroblast growth factor receptors (FGFRs) are transmembrane receptor tyrosine kinases that regulate multiple physiological processes. Aberrant activation of FGFR2 and FGFR3 has been linked to the pathogenesis of many tumor types, including cholangiocarcinoma and bladder cancer. Current therapies targeting the FGFR2/3 pathway exploiting small-molecule kinase inhibitors are associated with adverse events due to undesirable inhibition of FGFR1 and FGFR4.

Potent and Selective Biaryl Amide Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1).

Herein we report the discovery of a novel biaryl amide series as selective inhibitors of hematopoietic protein kinase 1 (HPK1). Structure-activity relationship development, aided by molecular modeling, identified indazole as a core for further exploration because of its outstanding enzymatic and cellular potency coupled with encouraging kinome selectivity. Late-stage manipulation of the right-hand aryl and amine moieties surmounted issues of selectivity over TRKA, MAP4K2, and STK4 as well as generating compounds with balanced ADME profiles and promising pharmacokinetics.

Discovery of Pyrazolopyridine Derivatives as HPK1 Inhibitors.

In spite of the great success of immune checkpoint inhibitors in immune-oncology therapy, an urgent need still exists to identify alternative approaches to broaden the scope of therapeutic coverage. Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1, functions as a negative regulator of activation signals generated by the T cell antigen receptor. Herein we report the discovery of novel pyrazolopyridine derivatives as selective inhibitors of HPK1.

Elucidation of the bioactive conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of mu-opioid receptor antagonists.

The series of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have been widely investigated as opioid receptor antagonists. One of our research goals was to explore the bioactive conformation of the N-phenethyl trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine derivative 3, prototypical mu-opioid antagonist in this series. In this effort, the rotational degrees of freedom of the N-substituent of 3 were limited by incorporation of an ethylene bridge between the piperidine 2- or 6-position of 3 and the benzylic position of the N-phenethyl moiety.

Synthesis and structure-activity relationships of a new series of 2alpha-substituted trans-4,5-dimethyl-4-(3-hydroxyphenyl)piperidine as mu-selective opioid antagonists.

Structure-activity relationships at the 2alpha-position of the piperidine ring of the trans-4,5-dimethyl-4-(3-hydroxyphenyl)piperidine mu-opioid antagonist series were investigated. This study showed that only small linear alkyl groups (methyl, propyl) are tolerated at the 2alpha-position of the piperidine ring of this series.

Photo-caged agonists of the nuclear receptors RARgamma and TRbeta provide unique time-dependent gene expression profiles for light-activated gene patterning.

Light-activated gene expression systems hold promise as new tools for studying spatial and temporal gene patterning in multicellular systems. Photo-caged forms of nuclear receptor agonists have recently been shown to mediate photo-dependent transcription in mammalian cells, however, because intracellularly released agonists can rapidly diffuse out of cells, the photo-initiated transcription response is only transient and limited to only a few hours in reported examples. Herein we describe a photo-caged thyroid hormone receptor agonist that provides a robust 36 h transcription response to a single irradiation event.

The solid-phase synthesis and use of N-monosubstituted piperazines in chemical library synthesis.

An efficient solid-phase synthesis of mono-N-substituted piperazines is presented. The key transformation involves a selective borane amide bond reduction in the presence of a carbamate resin linkage. This synthetic route takes advantage of the large diverse pool of commercially available carboxylic acids, acid chlorides, and sulfonyl chlorides.