An Expeditious Synthesis of the MDM2–p53 Inhibitor AM-8553

The development of the structurally complex MDM2/p53 inhibitor AM-8553 was impeded by the low yield of the initial synthesis. A second generation synthesis is described that features a Noyori dynamic kinetic resolution, a highly diastereoselective allylation, and a novel oxazoline-assisted piperidinone forming reaction to provide AM-8553 in 35.6% yield and 11 steps

Discovery of AM-1638: A Potent and Orally Bioavailable GPR40/FFA1 Full Agonist

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (<b>1</b>), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist <b>1</b> to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (<b>21</b>). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist <b>21</b> exhibits in BDF/DIO mice as compared to partial agonist <b>1</b>

Optimization of GPR40 Agonists for Type 2 Diabetes

GPR40 (FFA1 and FFAR1) has gained significant interest as a target for the treatment of type 2 diabetes. TAK-875 (<b>1</b>), a GPR40 agonist, lowered hemoglobin A1c (HbA1c) and lowered both postprandial and fasting blood glucose levels in type 2 diabetic patients in phase II clinical trials. We optimized phenylpropanoic acid derivatives as GPR40 agonists and identified AMG 837 (<b>2</b>) as a clinical candidate. Here we report our efforts in searching for structurally distinct back-ups for AMG 837. These efforts led to the identification of more polar GPR40 agonists, such as AM-4668 (<b>10</b>), that have improved potency, excellent pharmacokinetic properties across species, and minimum central nervous system (CNS) penetration

5‑Alkyl-2-urea-Substituted Pyridines: Identification of Efficacious Glucokinase Activators with Improved Properties

Two 1-(4-aryl-5-alkyl-pyridin-2-yl)-3-methylurea glucokinase activators were identified with robust <i>in vivo</i> efficacy. These two compounds possessed higher solubilities than the previously identified triaryl compounds (i.e., <b>AM-2394</b>). Structure–activity relationship studies are presented along with relevant pharmacokinetic and <i>in vivo</i> data

Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ Inhibitors

Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, <b>1</b> (AM-8508) and <b>2</b> (AM-9635), with good pharmacokinetic properties. The compounds inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compounds which share a benzimidazole bicycle are effective when administered in vivo at unbound concentrations consistent with their in vitro cell potency as a consequence of improved unbound drug concentration with lower unbound clearance. Furthermore, the compounds demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inbibitors <b>1</b> and <b>2</b> led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH

Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394

Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure–activity relationships leading to the discovery of <b>AM-2394</b>, a structurally distinct GKA. <b>AM-2394</b> activates GK with an EC₅₀ of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an <i>ob/ob</i> mouse model of diabetes

Aminopyrazole–Phenylalanine Based GPR142 Agonists: Discovery of Tool Compound and in Vivo Efficacy Studies

Herein, we report the lead optimization of amrinone–phenylalanine based GPR142 agonists. Structure–activity relationship studies led to the discovery of aminopyrazole–phenylalanine carboxylic acid <b>22</b>, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability. Compound <b>22</b>, together with its orally bioavailable ethyl ester prodrug <b>23</b>, were found to be suitable for in vivo proof-of-concept studies. Compound <b>23</b> displayed good efficacy in a mouse oral glucose tolerance test (OGTT). Compound <b>22</b> showed GPR142 dependent stimulation of insulin secretion in isolated mouse islets and demonstrated a statistically significant glucose lowering effect in a mouse model bearing transplanted human islets

Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists

We recently reported the discovery of a potent GPR40 full agonist AM-1638 (<b>1</b>). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound <b>8</b> and <b>20</b> also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties

Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2–p53 Interaction

Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone–pyridine inhibitors <b>6</b>, <b>7</b>, <b>14</b>, and <b>15</b> with improved pharmacokinetic properties in rats. Reducing structure complexity of the <i>N</i>-alkyl substituent led to the discovery of <b>23</b>, a potent and simplified inhibitor of MDM2. Compound <b>23</b> exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model

Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles

GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism leading to little risk of hypoglycemia. We recently reported the discovery of AM-1638 (<b>2</b>), a potent full agonist of GPR40. In this report, we present the discovery of GPR40 full agonists containing conformationally constrained tricyclic spirocycles and their structure–activity relationships leading to more potent agonists such as AM-5262 (<b>26</b>) with improved rat PK profile and general selectivity profile. AM-5262 enhanced glucose stimulated insulin secretion (mouse and human islets) and improved glucose homeostasis in vivo (OGTT in HF/STZ mice) when compared to AM-1638