Compounds of formula (I) inhibit the activity of endothelin. The symbols are defined as follows: R?1, R2, R3 and R4? are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z?1, Z2 and Z3?; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(O)H or -C(O)R5; (h) -CO?2?H or -CO2R?5?; (i) -Z4-NR6R7; (j) -Z?4-N(R10)-Z5-NR8R9?; or (k) R?3 and R4? together may also be alkylene or alkenylene, either of which may be substituted with Z?1, Z2 and Z3?, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; and the remaining symbols are as defined in the specification.

Substituted biphenyl isoxazole sulfonamides

Fibroblast activation protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncology applications. We previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, we explore in detail the structure–activity relationship around this core scaffold. We report extensively optimized compounds that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP). The log D values, plasma stabilities, and microsomal stabilities of selected compounds were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral ...

Extended Structure–Activity Relationship and Pharmacokinetic Investigation of (4-Quinolinoyl)glycyl-2-cyanopyrrolidine Inhibitors of Fibroblast Activation Protein (FAP)

Novel biphenyl sulfonamide compounds which are combined angiotensin and endothelin receptor antagonists are claimed along with methods of using such compounds in the treatment of conditions such as hypertension and other diseases, as well as pharmaceutical compositions containing such compounds.

Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists

Natural products as immunosuppressive agents

For the planning of an organic synthesis route, the disconnection approach guided by retrosynthetic analysis of possible intermediates and the chemical reactions involved, back to ready available starting materials, is well established In contrast, such concepts just get developed for biocatalytic routes In this Review we highlight functional group interconversions catalyzed by enzymes The article is organized rather by chemical bonds formed-exemplified for C-N, C-O- and C-C-bonds-and not by enzyme classes, covering a broad range of reactions to incorporate the desired functionality in the target molecule Furthermore, the successful use of biocatalysts, also in combination with chemical steps, is exemplified for the synthesis of various drugs and advanced pharmaceutical intermediates such as Crispine A, Sitagliptin and Atorvastatin This Review also provides some basic guidelines to choose the most appropriate enzyme for a targeted reaction keeping in mind aspects like commercial availability, cofactor-requirement, solvent tolerance, use of isolated enzymes or whole cell recombinant microorganisms aiming to assist organic chemists in the use of enzymes for synthetic applications

https://onlinelibrary.wiley.com/doi/pdf/10.1002/chem.201702235

A Retrosynthesis Approach for Biocatalysis in Organic Synthesis.

A practical method for the preparation of α′-chloroketones of N-carbamate protected-α-aminoacids

The present invention relates to a novel method useful for the conversion of amino acids to halomethylketones, which are then converted to amino acid epoxides. Such epoxides are important intermediates for the synthesis of inhibitors of renin and HIV protease, which are particularly useful in the treatment and/or prevention of HIV infection (AIDS).

Process for Preparing N-Protected Amino Acid Alpha-Halomethyl Ketones and Alcohols from N-Protected Amino Acid Esters

: Claisen condensation of the dianion of chloroacetic acid with N-BOC a -amino acid methyl esters provides the corresponding a -chloroketones in high yield and enantiomeric excess.

Preparation of α‐Chloroketones by the Chloroacetate Claisen Reaction.

Methods for the preparation of biphenyl isoxazole sulfonamides and intermediates thereof. The present invention also relates to the novel intermediates prepared by these methods. The biphenyl isoxazole sulfonamides prepared by the present methods are endothelin antagonists useful, inter alia, for the treatment of hypertension.

Methods for the preparation of biphenyl isoxazole sulfonamides

An efficient synthesis of the ( S )-(−)- and ( R )-(+)-enantiomers of 15-deoxyspergualin (15-DSG) is reported. The synthesis involves preparative HPLC separation and subsequent hydrogenolysis of two diastereoisomers 10a and 10b of fully protected 15-DSG penultimates. Alternatively, diastereomerically pure amide 10b (97% de) was also prepared from acid 8b (97% de), which was obtained via crystallization of a 1:1 diastereomeric mixture of 8a and 8b .

Efficient synthesis of (S)-(−)- and (R)-(+)-enantiomers of 15-deoxyspergualin (15-DSG)

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