A General Approach to Optically Pure, α-Methyl Non-Natural Amino Acids: Enabling Unique Peptides as Drug Candidates.

An α-methyl, non-natural amino acid (NNAA) building block equipped with an alkyl halide tail that could be readily transformed into an organozinc was prepared. This single organometallic was cross-coupled to an array of heterocyclic electrophiles using the Pd-PEPPSI-IHept catalyst to produce a wide selection of optically pure α-methyl NNAAs. With these in hand, non-natural peptides are being produced for evaluation in a variety of therapeutic areas in drug discovery.

The History of Flow Chemistry at Eli Lilly and Company.

Flow chemistry was initially used for speed to early phase material delivery in the development laboratories, scaling up chemical transformations that we would not or could not scale up batch for safety reasons. Some early examples included a Newman Kwart Rearrangement, Claisen rearrangement, hydroformylation, and thermal imidazole cyclization. Next, flow chemistry was used to enable safe scale up of hazardous chemistries to manufacturing plants.

A Continuous Flow Process for LSN647712 via Double Organometallic Additions to Dimethylcarbamyl Chloride.

The ketone intermediate LSN647712 is a key synthetic intermediate for the drug substance lasmiditan manufacturing process. A three-step connected continuous flow process utilizing a Turbo Grignard reagent, -methylpiperidin-4-ylmagnesium chloride, and lithiated 2,6-dibromopyridine sequentially added to double electrophile (O═C(++) synthon dimethylcarbamyl chloride (DMCC) was developed to deliver the ketone intermediate in a high chemical yield (>85%). This highly productive (>100 g/h lab system) and intensified process (τ ∼ 3 min) yields the product in high purity upon batch reactive crystallization to form a corresponding hydrobromide salt.

Assessing needs for psychiatric treatment in prisoners: 2. Met and unmet need.

Background: In a companion paper, we established high levels of psychiatric morbidity in prisoners (Bebbington et al. Soc Psychiatry Psychiatr Epidemiol, 2016). In the current report, we evaluate how this morbidity translates into specific needs for treatment and the consequent implications for services.

Assessing needs for psychiatric treatment in prisoners: 1. Prevalence of disorder.

Background: High levels of psychiatric morbidity in prisoners have important implications for services. Assessing Needs for Psychiatric Treatment in Prisoners is an evaluation of representative samples of prisoners in a male and a female prison in London. This paper reports on the prevalence of mental disorders.

Scope of the asymmetric intramolecular stetter reaction catalyzed by chiral nucleophilic triazolinylidene carbenes.

A highly enantioselective intramolecular Stetter reaction of aromatic and aliphatic aldehydes tethered to different Michael acceptors has been developed. Two triazolium scaffolds have been identified that catalyze the intramolecular Stetter reaction with good reactivity and enantioselectivity. The substrate scope has been examined and found to be broad; both electron-rich and -poor aromatic aldehydes undergo cyclization in high yield and enantioselectivity.

An efficient synthesis of achiral and chiral 1,2,4-triazolium salts: bench stable precursors for N-heterocyclic carbenes.

[reaction: see text] The promising utility of triazolyl N-heterocyclic carbene catalysts in umpolung aldehyde chemistry requires a straightforward reliable synthesis from readily available materials. Herein, we describe the synthesis of a variety of triazolyl N-heterocyclic carbene precursors. The reactions commence from commercially available amino acids and proceed in 44-68% overall yields.

Enantioselective synthesis of quaternary stereocenters via a catalytic asymmetric Stetter reaction.

A new electron-deficient chiral triazolium salt has been shown to catalyze the formation of quaternary stereocenters by an asymmetric intramolecular Stetter reaction. Pentafluorophenyl substitution on an aminoindanol-derived catalyst affords tertiary ether, thioether, and quaternary stereocenters in typically greater than 90% ee and very good chemical yield. Aromatic and aliphatic aldehydes are equally competent substrates for this reaction.

Contributions of nitric oxide synthase isozymes to exhaled nitric oxide and hypoxic pulmonary vasoconstriction in rabbit lungs.

We investigated the source(s) for exhaled nitric oxide (NO) in isolated, perfused rabbits lungs by using isozyme-specific nitric oxide synthase (NOS) inhibitors and antibodies. Each inhibitor was studied under normoxia and hypoxia. Only nitro-L-arginine methyl ester (L-NAME, a nonselective NOS inhibitor) reduced exhaled NO and increased hypoxic pulmonary vasoconstriction (HPV), in contrast to 1400W, an inhibitor of inducible NOS (iNOS), and 7-nitroindazole, an inhibitor of neuronal NOS (nNOS).

Inhibition of aquaporin-mediated CO2 diffusion and voltage-gated H+ channels by zinc does not alter rabbit lung CO2 and NO excretion.

Aquaporins (AQs) increase cell membrane CO(2) diffusivity, and it has been proposed that they may serve as transmembrane channels for CO(2) and other small gas molecules. In addition, it has been hypothesized that voltage-gated H(+) channels located on the apical membrane of the alveolar epithelium contribute to CO(2) elimination by the lung. To test whether these membrane proteins contribute to CO(2) elimination in vivo, we measured CO(2) exchange in buffer- and blood-perfused rabbit lungs before and after addition of 0.

Effects of S-nitrosation and cross-linking of hemoglobin on hypoxic pulmonary vasoconstriction in isolated rat lungs.

Free hemoglobin (Hb) and red blood cells augment hypoxic pulmonary vasoconstriction (HPV) by scavenging nitric oxide (NO). S-nitrosation of Hb (SNO-Hb) may confer vasodilatory properties by allowing release of NO during deoxygenation and/or by interaction with small-molecular weight thiols. Likewise, cross-linking of free Hb may limit its vasoconstrictive effect by preventing abluminal movement of the molecule.

A highly enantioselective catalytic intramolecular Stetter reaction.

A family of chiral triazolium salts has been developed for inducing the asymmetric intramolecular Stetter reaction. The use of an aminoindanol-derived catalyst affords optimal results, with the product keto esters formed in 82-97% ee and very good chemical yield. Aromatic and aliphatic aldehydes are equally competent substrates for this reaction.

The effect of a bioresorbable matrix barrier in endodontic surgery on the rate of periapical healing: an in vivo study.

The purpose of this prospective clinical study was to assess the rate of healing of periapical bony defects created at the time of endodontic periapical surgery by measuring the densitometric ratio change in periapical osseous tissues, after periapical endodontic surgery was performed, by using or not using Guidor bioresorbable membrane material. Periapical surgeries were performed on 25 patients where nonsurgical root canal therapy had failed and a periapical lesion was present. For inclusion in the study, the osseous defect to be analyzed had to be confined to the apical area, with bone covering the entire root surface coronally, and an intact lingual cortical plate had to be present.