Merck

This initial lead showed potent binding affinity to CCR5 (IC50 35 nM), but only weak, micromolar activity in a PBMC viral replication assay, with a dose analog also showing very low oral bioavaUability in rat [40, 41]. Development of SAR through 

This concluded an impressive and comprehensive SAR survey around the initial HTS hit through to a development candidate. Subsequent publications from the Merck group have indicated the compound to be hepatotoxic in predinical rat studies at elevated doses, implying a mechanism of mitochondrial inhibition and explaining the discontinuation of Merck A [58]. 

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A nematic liquid crystal cell, based on Merck Licrilite E202, was used in these experiments. The rod like liquid crystal molecules preferentially aligned themselves with each other and to an alignment surface in the liquid crystal device. Any birefringence. An, was given as the difference between the two orthogonal refractive indices. As a consequence, any resulting... 

MRCK Merck Co., Inc., USA descriptions of chemicals, drugs, agricultural and natural products sub- stance, numeric 10000 Merck Index (encyclo- pedia) STN semian- nually wuw.cas.org/ ONLINE/ BBSS/ mrcfess.htrnl... 

Inadequate availability of experimental data can considerably inhibit the development of improved energy functions for more accurate simulations of energetic, structural, and spectroscopic properties. This has led to the development of class II force fields such as CFF and the Merck Molecular Force Field (MMFF), which are both based primarily on quantum mechanical calculations of the energy surface. The purpose of MMFF, which has been developed by Thomas Halgren at Merck and Co., is to be able to handle all functional groups of interest in pharmaceutical design. 

The model described above is based on the Huuskemen data set. Later we obtained an additional data set. compiled by tbe company Merck TCGaA. We wanted to know how structurally similar these two data sets are. Thus, the following work was per-fonned. 

This then led us to develop a solubility model based on the Merck data set [32]. 

Figure 10.1-4. Distribution of compounds from two data sets in the same KNN (Kohonen s self-organizing neural network) map by using 18 topological descriptors as input descriptors, where 1 represents the 1588 compounds in the Merck data set (excluding those compounds that are also in the Huuskonen data set) 2 represents the 799 compounds in the Huuskonen data set (excluding those compounds that are also in the Merck data set), and 3 represents the overlapping part of the Huuskonen data set and the Merck data set.

Halgren T A 1996a. Merck Molecular Force Field I. Basis, Form, Scope, Parameterisation and Performance of MMFF94. Journal of Computational Chemistry 17 490-519. 

Halgren T A 1996b. Merck Molecular Force Field II MMEF94 van der Waals and Electrostatic Parameters for Intermolecular Interactions. Journal of Computational Chemistry 17 520-552. 

An impressive example of the application of structure-based methods was the design of a inhibitor of the HIV protease by a group of scientists at DuPont Merck [Lam et al. 1994 This enzyme is crucial to the replication of the HIV virus, and inhibitors have bee shown to have therapeutic value as components of anti-AIDS treatment regimes. The star1 ing point for their work was a series of X-ray crystal structures of the enzyme with number of inhibitors boimd. Their objective was to discover potent, novel leads whid were orally available. Many of the previously reported inhibitors of this enzyme possessei substantial peptide character, and so were biologically unstable, poorly absorbed am rapidly metabolised. 

Cyclopentadiene (2.5) was prepared from its dimer (Merck-Schuchardt) immediately before use. Dimineralised water was distilled twice in a quartz distillation unit. Ethanol (Merck) was of the highest purity available. Acetonitrile (Janssen) was mn over basic aluminium oxide prior to use. 2,2,2-Trifluoroethanol (Acros) was purified by distillation (bp 79 - C). Co(N03)2 6H20,... 

Pyridyl)hydrazine (Aldrich), 4-acetylpyridine (Acros), N,N,N -trimethylethylenediamine (Aldrich), methylrhenium trioxide (Aldrich), InQj (Aldrich), Cu(N0j)2-3H20 (Merck), Ni(N03)2-6Il20 (Merck), Yb(OTf)3(Fluka), Sc(OTf)3 (Fluka), 2-(aminomethyl)pyridine (Acros), benzylideneacetone (Aldrich), and chalcone (Aldrich) were of the highest purity available. Borane dimethyl sulfide (2M solution in THE) was obtained from Aldrich. Methyl vinyl ketone was distilled prior to use. Cyclopentadiene was prepared from its dimer immediately before use. (R)-l-acetyl-5-isopropoxy-3-pyrrolin-2-one (4.15) has been kindly provided by Prof H. Hiemstra (University of Amsterdam). 

The Merck molecular force field (MMFF) is one of the more recently published force fields in the literature. It is a general-purpose method, particularly popular for organic molecules. MMFF94 was originally intended for molecular dynamics simulations, but has also seen much use for geometry optimization. It uses five valence terms, one of which is an electrostatic term, and one cross tenn. 

The MM2, MM3, and Merck (MMFF) force fields perform best for a wide range of organic molecules. 

According to the Merck, and "Essential Oils" by Guenther, Sassafras Oil is composed of the following ... 

One final thought. Strike found that there are a lot of companies that do not sell sodium bisulfite (NaHSOa). In fact, a lot of companies list sodium bisulfite in their catalogs but tell the reader to see sodium metabisulfite instead because that is the only form of this compound they carry. In other words, a lot of companies sell sodium metabisulfite (NaaSaOs) as an acceptable alternative to the other. The Merck Index even says about sodium bisulfite that the [sodium] bisulfite of commerce consists chiefly of sodium metabisulfite, Nd2S20s, and for all practical purposes possesses the same properties as the true bisulfite". What this meant to Strike was that metabisulfite would work just as well. So some was purchased and tried. And it really does work just the samel... 

Bromosafrole is a great stepping stone to final product and was, in fact, the exact precursor used by Merck who was the first person to synthesize MDMA. Until very recently it was the defacto method that most underground chemists started out with (Someone-Who-Is-Not-Strike included) because, at first glance, it seems so simple and uses basic chemicals and equipment. Once someone has the bromosafrole, all one has to do is just swap out that Br with simple ammonia or methylamine and the deed is done. 

But the key to success Is getting the right form of HBr for the reaction. A lot of people start off with the CA abstract that uses aqueous 70% HBr as the reagent (this abstract is essentially a rewrite of Merck s original patent) [59], The following is the write up ... 

Nitroethane and 1-(3,4 methylenedioxy) 2- nitropropane This method of producing the above mentioned nitro compounds is by far the best Ritter has come across yet The problem with standard nitroethane synthesis is that the -NO2 source most commonly used is silver nitrite (a la Merck Index citing). Needless to say, this is going to be an expensive compound to make as it is not available commercially but must be synthesized from costly silver nitrate. The other methods mentioned in Vogels 5th masterpiece... 

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