Research at Merck

Medicinal chemistry has frequently drawn inspiration and important new leads from the examination of natural products, and this was proven to be the case once more. In 1992, researchers at Merck and Glaxo announced, almost simultaneously, the independent discovery of the same new class of natural products from two different fungi. As a consequence, the same family of natural products has two names - the zaragozic acids (Merck)4 or the squalestatins (Glaxo).5 A typical member of the family, zaragozic acid A (squa-lestatin SI) (1) was shown to have a tremendous affinity for squalene synthase (K, = 79 pM for rat microsomal squalene synthase) and could even lower serum cholesterol levels in vivo in a population of marmosets.6... 

Researchers at Merck Co. [35] who, together with scientists from Solvias, had developed the enantioselective hydrogenation of unprotected enamine amides and esters [36], reported a more recent example of product inhibition. The product amine amide or ester was found to be an inhibitor of the catalyst, and indeed instances of catalyst poisoning by amines have been reported several times (see later). The authors also found an excellent solution to this problem the addition of BOC-anhydride to the hydrogenation reaction neatly reacts away all the amine to form the BOC-protected amine, whereas the enamine was left unreacted (Scheme 44.4). This addition resulted in a remarkable rate enhancement [35]. 

Gompounds that inhibit Akt-1 are of increasing interest as possible oncology therapeutics [59]. Akt-1 is a multi-domain protein that is known to be activated after binding of its pleckstrin homology (PH) domain to its endogenous target. A report from researchers at Merck indicates that their Akt-1 inhibitor does... 

Researchers at Merck developed a series of benzothiophen-2-yl hydroxamic acids as HDACis [44] tvhich can be considered a hybrid of the cinnamyl and thiophenyl hydroxamic acids. Starting from simple acetyl hydroxamic acid (33a IC50 = 625 pM), they shotved that incremental boost in activity could be achieved introducing first a phenyl ring (IC50 = 20 pM), then replacing this tvith a thiophene (IC50 = 6.6 pM). 

For an excellent review about process research at Merck, see E. J. J. Grabowski, ACS Symposium Series 2004, 870 (Chemical Process Research), 1—21. 

Researchers at Merck have studied the synthesis of the simple carbapenem system (94) through Wittig cyclization of the keto ylide (93). This interesting precursor was prepared directly from the thiol ester... 

Research at Merck Frosst in 1989 (165, 166) led to the initial FLAP inhibitor, MK0886 (14), and consequently to the discovery of FLAP itself MK0886 was derived from a... 

Protease substrate libraries can provide useful information about the enzyme sub-site preferences which can be applied to inhibitor design [268, 387-392]. Researchers at Merck have applied positonal-scanning combinatorial substrate libraries to identify an optimal substrate (Ac-WEHD-ACM) for caspase-1 which is a cysteine protease implicated in inflammation and apoptosis [390, 391], This information was then used to generate the po-... 

The palladium-catalyzed coupling of vinyl triflates with amides, carbamates, and sulfonamides has been reported by researchers at Merck.119 They identified Xantphos as the best ligand for this reaction. The product enamides serve as valuable synthetic intermediates as they can undergo asymmetric hydrogenation to give enantiopure amines. 

Researchers at Merck (24) sought to develop compounds that lacked the sulfhydryl group of captopril yet maintained some ability to chelate zihc. Compounds having the geheral structure shown below were designed to meet this objective. 

In middle of the 1980s, efficient asymmetric phase-transfer reactions using catalytic amounts of Al-benzylcinchoninium chlorides were developed by researchers at Merck. This catalyst was able to alkylate 2-substituted-2-phenyl indanones with high ee (up to 94% ee) [20]. 

Copper catalysts for the formation of biaryl ethers have also been developed that contain diketonate ligands. Researchers at Merck Laboratories reported the coupling of aryl halides with phenols catalyzed by the combination of CuCl and 2,2,6,6-tetramethylhep-tane-3,5-dione (TMHD), which generates a copper diketonate catalyst (Equation 19.111). Catalysts containing related O-donor ligands have also been used. Two examples of reactions conducted with a polyol and with a phosphonic acid as ligand are shown in Equation 19.112 and Equation 19.113. ... 

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