Synthesis and Evaluation of the Metabolites of AMG 221, a Clinical Candidate for the Treatment of Type 2 Diabetes

All eight of the major active metabolites of (<i>S</i>)-2-((1<i>S</i>,2<i>S</i>,4<i>R</i>)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5<i>H</i>)-one (AMG 221, compound <b>1</b>), an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 that has entered the clinic for the treatment of type 2 diabetes, were synthetically prepared and confirmed by comparison with samples generated in liver microsomes. After further profiling, we determined that metabolite <b>2</b> was equipotent to <b>1</b> on human 11β-HSD1 and had lower in vivo clearance and higher bioavailability in rat and mouse. Compound <b>2</b> was advanced into a pharmacodynamic model in mouse where it inhibited adipose 11β-HSD1 activity

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 3. Structure–Activity Relationships within the Aryl Carbinol Region of the <i>N</i>‑Arylsulfonamido‑<i>N</i>′‑arylpiperazine Series

We have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, glucokinase regulatory protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2<i>S</i>)-4-((6-amino-3-pyridinyl)­sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)­phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (<b>1</b>, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound <b>1</b> bound to hGKRP, we identified several potent GK–GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives <b>24</b> and <b>29</b> possessed excellent potency as well as favorable PK properties. When dosed orally in <i>db</i>/<i>db</i> mice, both compounds significantly lowered fed blood glucose levels (up to 58%)

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept

Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide <b>25</b> (AMG-1694). When dosed in ZDF rats, <b>25</b> showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 2. Leveraging Structure-Based Drug Design to Identify Analogues with Improved Pharmacokinetic Profiles

In the previous report, we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of <b>1</b> (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (<b>27</b>, AMG-3969). When administered to <i>db</i>/<i>db</i> mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels

Oxopyrido[2,3‑<i>d</i>]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

In nonsmall cell lung cancer (NSCLC), the threonine⁷⁹⁰–methionine⁷⁹⁰ (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido­[2,3-<i>d</i>]­pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound <b>24</b> which potently inhibits gefitinib-resistant EGFR^L858R,T790M with 100-fold selectivity over wild-type EGFR. Compound <b>24</b> displays strong antiproliferative activity against the H1975 nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFR^L858R,T790M driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR

Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) Binding: Strategic Use of a N → S (n_N → σ*_S–X) Interaction for Conformational Constraint

The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK–GKRP disrupters are revealed. Diarylmethane­sulfonamide hit <b>6</b> (hGK–hGKRP IC₅₀ = 1.2 μM) was optimized to lead compound <b>32</b> (AMG-0696; hGK–hGKRP IC₅₀ = 0.0038 μM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (n_N → σ*_S–X) in <b>32</b> was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound <b>32</b> was shown to induce GK translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = −45%; 100 mg/kg po, 3 h). X-ray analyses of <b>32</b> and several precursors bound to GKRP were also obtained. This novel disrupter of GK–GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design