4 research outputs found
Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology
Small molecule toll-like receptor
(TLR) 7 agonists have gathered
considerable interest as promising therapeutic agents for applications
in cancer immunotherapy. Herein, we describe the development and optimization
of a series of novel TLR7 agonists through systematic structure–activity
relationship studies focusing on modification of the phenylpiperidine
side chain. Additional refinement of ADME properties culminated in
the discovery of compound 14, which displayed nanomolar
reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic
profiles and synergistic antitumor activity when administered in combination
with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents
Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology
We have designed and developed novel and selective TLR7
agonists
that exhibited potent receptor activity in a cell-based reporter assay. In vitro, these agonists significantly induced secretion
of cytokines IL-6, IL-1β, IL-10, TNFa, IFNa, and IP-10 in human
and mouse whole blood. Pharmacokinetic and pharmacodynamic studies
in mice showed a significant secretion of IFNα and TNFα
cytokines. When combined with aPD1 in a CT-26 tumor model, the lead
compound showed strong synergistic antitumor activity with complete
tumor regression in 8/10 mice dosed using the intravenous route. Structure–activity
relationship studies enabled by structure-based designs of TLR7 agonists
are disclosed
Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists
G protein-coupled
receptor 40 (GPR40) has become an attractive
target for the treatment of diabetes since it was shown clinically
to promote glucose-stimulated insulin secretion. Herein, we report
our efforts to develop highly selective and potent GPR40 agonists
with a dual mechanism of action, promoting both glucose-dependent
insulin and incretin secretion. Employing strategies to increase polarity
and the ratio of sp<sup>3</sup>/sp<sup>2</sup> character of the chemotype,
we identified BMS-986118 (compound <b>4</b>), which showed potent
and selective GPR40 agonist activity <i>in vitro</i>. <i>In vivo</i>, compound <b>4</b> demonstrated insulinotropic
efficacy and GLP-1 secretory effects resulting in improved glucose
control in acute animal models
Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode
A novel series of pyrrolidine-containing
GPR40 agonists is described
as a potential treatment for type 2 diabetes. The initial pyrrolidine
hit was modified by moving the position of the carboxylic acid, a
key pharmacophore for GPR40. Addition of a 4-<i>cis</i>-CF<sub>3</sub> to the pyrrolidine improves the human GPR40 binding <i>K</i><sub>i</sub> and agonist efficacy. After further optimization,
the discovery of a minor enantiomeric impurity with agonist activity
led to the finding that enantiomers <b>(</b><i><b>R,R</b></i><b>)-68</b> and <b>(</b><i><b>S,S</b></i><b>)-68</b> have differential effects on the radioligand
used for the binding assay, with <b>(</b><i><b>R,R</b></i><b>)-68</b> potentiating the radioligand and <b>(</b><i><b>S,S</b></i><b>)-68</b> displacing
the radioligand. Compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b> activates both
G<sub>q</sub>-coupled intracellular Ca<sup>2+</sup> flux and G<sub>s</sub>-coupled cAMP accumulation. This signaling bias results in
a dual mechanism of action for compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b>, demonstrating glucose-dependent insulin and GLP-1 secretion in
vitro. In vivo, compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b> significantly lowers
plasma glucose levels in mice during an oral glucose challenge, encouraging
further development of the series