Performance Modeling of Experimental Laser Lightcrafts

A computational plasma aerodynamics model is developed to study the performance of a laser propelled Lightcraft. The computational methodology is based on a time-accurate, three-dimensional, finite-difference, chemically reacting, unstructured grid, pressure-based formulation. The underlying physics are added and tested systematically using a building-block approach. The physics modeled include non-equilibrium thermodynamics, non-equilibrium air-plasma finite-rate kinetics, specular ray tracing, laser beam energy absorption and refraction by plasma, non-equilibrium plasma radiation, and plasma resonance. A series of transient computations are performed at several laser pulse energy levels and the simulated physics are discussed and compared with those of tests and literatures. The predicted coupling coefficients for the Lightcraft compared reasonably well with those of tests conducted on a pendulum apparatus

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

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

Discovery of AMG 232, a Potent, Selective, and Orally Bioavailable MDM2–p53 Inhibitor in Clinical Development

We recently reported the discovery of AM-8553 (<b>1</b>), a potent and selective piperidinone inhibitor of the MDM2–p53 interaction. Continued research investigation of the <i>N</i>-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 (<b>2</b>), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound <b>2</b> is an extremely potent MDM2 inhibitor (SPR <i>K</i>_D = 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)