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Background and Aims: Safe medication is an important part of anesthesia practice. Even though anesthesia practice has become safer with various patient safety initiatives, it is not completely secure from errors which can sometimes lead to devastating complications. Multiple reports on medication errors have been published; yet, there exists a lacuna regarding the quantum of these events occurring in our country or the preventive measures taken. Hence, we conducted a survey to study the occurrence of medication errors, incident reporting, and preventive measures taken by anesthesiologists in our country. Material and Methods: A self-reporting survey questionnaire (24 questions, 4 parts) was mailed to 9000 anesthesiologists registered in Indian Society of Anaesthesiologists via Survey Monkey Website. Results: A total of 978 completed surveys were returned for analysis (response rate = 9.2%). More than two-thirds (75.6%, n = 740) had experienced drug administration error and 7.7% (57) of respondents faced major morbidity and complications. Haste/Hurry (23.4%) was identified as the most common contributor to medication errors in the operation theater. Loading and double-checking of drugs before administration by concerned anesthesiologist were identified as safety measures to reduce drug errors. Conclusion: Majority of our respondents have experienced drug administration error at some point in their career. A small yet important proportion of these errors have caused morbidity/mortality to patients. The critical incident reporting system should be established for regular audits, an effective root cause analysis of critical events, and to propose measures to prevent the same in future.

GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs. Compound 24 demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.

An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (−)- 1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer’s disease. Specifically, 4-CF 3 and 4-Br substituted arylsulfone analogs, (−)- 1b and (−)- 1c , are equipotent to compound (−)- 1a . On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.

An efficient synthesis of fused morpholine oxadiazoline core structures was accomplished in an effort to identify optimum gamma secretase modulator leads in the treatment of Alzheimer’s disease. Reaction pathways were proposed for the key intramolecular cyclization reaction, and chemistry was designed to probe these hypotheses. A highly diastereoselective synthesis of potent GSM 27 was achieved. To further improve the synthesis, a second route was developed which successfully addressed the formation of a fused seven-member ring by-product, and provided opportunities to accelerate future SAR studies.

A new class of 2,6-disubstituted morpholine N-arylsulfonamide gamma-secretase inhibitors was designed based on the introduction of a morpholine core in lieu or piperidine in our lead series. This resulted in compounds with improved CYP 3A4 profiles. Several analogs that were active at lowering Abeta levels in Tg CRND8 mice upon oral administration were identified.

Development of cis-2,4,6-trisubstituted piperidine N-arylsulfonamides as γ-secretase inhibitors for the potential treatment of Alzheimer’s disease (AD) is reported.

Efficient asymmetric syntheses of both naturally occurring and non-naturally occurring enantiomers of gonioheptolide A are reported. The absolute configuration of (+)-gonioheptolide A was established by NOESY, Mosher ester analysis, and comparison with the specific rotation of the isolated (+)-gonioheptolide A.

The design and development of a new class of small 2,6-disubstituted piperidine N-arylsulfonamide gamma-secretase inhibitors is reported. Lowering molecular weight including the use of conformational constraint led to compounds with less CYP 3A4 liability compared to early leads. Compounds active orally in lowering Abeta levels in Tg CRND8 mice were identified as potential treatments for Alzheimer's disease.

Attachment of the cyclopropylcarbamate group to the piperidine core of gamma-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce Abeta levels in TgCRND8 mice after a single PO dosing at 30 mpk.

We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.

The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.

A novel series of tricyclic gamma-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous gamma-secretase inhibitors.

Efficient asymmetric syntheses of both naturally occurring and non-naturally occurring enantiomers of gonioheptolide A are reported. The absolute configuration of (+)-gonioheptolide A was established by NOESY, Mosher ester analysis, and comparison with the specific rotation of the isolated (+)-gonioheptolide A.