We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.
Lifetimes in water as short as 10(-11) s have been determined for carbocations and carbanions by referencing the rate of their reaction with solvent species to that for the appropriate "clock" reaction, and equilibrium constants have been determined as the ratio of rate constants for their formation and breakdown. Rate-equilibrium correlations for these organic ions are often poor and sometimes even defy the simple generalization that reactivity increases with decreasing stability. This seemingly confusing body of data can be understood through consideration of the both the Marcus intrinsic barrier and the thermodynamic driving force to reaction of these organic ions.
Type 2 diabetes is characterized by impaired glucose homeostasis due to defects in insulin secretion, insulin resistance and the incretin response. GPR40 (FFAR1 or FFA1) is a G-protein-coupled receptor (GPCR), primarily expressed in insulin-producing pancreatic β-cells and incretin-producing enteroendocrine cells of the small intestine. Several GPR40 agonists, including AMG 837 and TAK-875, have been disclosed, but no GPR40 synthetic agonists have been reported that engage both the insulinogenic and incretinogenic axes. In this report we provide a molecular explanation and describe the discovery of a unique and potent class of GPR40 full agonists that engages the enteroinsular axis to promote dramatic improvement in glucose control in rodents. GPR40 full agonists AM-1638 and AM-6226 stimulate GLP-1 and GIP secretion from intestinal enteroendocrine cells and increase GSIS from pancreatic islets, leading to enhanced glucose control in the high fat fed, streptozotocin treated and NONcNZO10/LtJ mouse models of type 2 diabetes. The improvement in hyperglycemia by AM-1638 was reduced in the presence of the GLP-1 receptor antagonist Ex(9–39)NH2.
A discovery program targeting respiratory
syncytial virus (RSV)
identified C-nucleoside 4 (RSV A2 EC50 = 530 nM) as a phenotypic screening lead targeting the RSV
RNA-dependent RNA polymerase (RdRp). Prodrug exploration resulted
in the discovery of remdesivir (1, GS-5734) that is >30-fold
more potent than 4 against RSV in HEp-2 and NHBE cells.
Metabolism studies in vitro confirmed the rapid formation of the active
triphosphate metabolite, 1-NTP, and in vivo
studies in cynomolgus and African Green monkeys demonstrated a >10-fold
higher lung tissue concentration of 1-NTP following molar
normalized IV dosing of 1 compared to that of 4. A once daily 10 mg/kg IV administration of 1 in an
African Green monkey RSV model demonstrated a >2-log10 reduction
in the peak lung viral load. These early data following the discovery
of 1 supported its potential as a novel treatment for
RSV prior to its development for Ebola and approval for COVID-19 treatment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.