E-value and Identity Cut-offs.

<p>E-value and Identity Cut-offs.</p

Comparison of four computational methods for integrating taxonomic information.

<p>MLE stands for the maximum likelihood estimation method, MSC stands for the Minimum Set Covering method, MLE of MCS stands for the MSC method followed by the MLE method, and NN stands for the nearest neighbor method. Each data point indicates the sensitivity and specificity achieved by one simulated dataset using corresponding method.</p

Rarefaction curve of lean and obese samples.

<p>Error bars indicating 95% confidence interval.</p

Discovery and in Vivo Evaluation of Dual PI3Kβ/δ Inhibitors

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue <b>63</b> was a potent and selective PI3Kβ/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue <b>63</b> was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kβ and δ isoforms in the treatment of a number of inflammatory diseases

Discovery of 6‑Phenylpyrimido[4,5‑<i>b</i>][1,4]oxazines as Potent and Selective Acyl CoA:Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitors with in Vivo Efficacy in Rodents

The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido­[4,5-<i>b</i>]­[1,4]­oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid <b>1</b>, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of <b>1</b> was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane <b>42</b>, which displayed significantly improved DGAT1 inhibition compared to <b>1</b>. Spiroindane <b>42</b> was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies

Discovery and in Vivo Evaluation of the Potent and Selective PI3Kδ Inhibitors 2‑((1<i>S</i>)‑1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro‑<i>N</i>‑methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-0687) and 2‑((1<i>S</i>)‑1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-5-fluoro‑<i>N</i>‑methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-1430)

Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, <b>4</b>, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, <b>6a</b> (AM-0687) and <b>7</b> (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of <b>6a</b> and <b>7</b> in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either <b>6a</b> or <b>7</b> resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development