Iron is an essential cause of fishy aftertaste formation in wine and seafood pairing.

Fishy aftertaste is sometimes perceived in wine with fish and seafood pairing. However, what component of wine clashes with seafood or what compound contributes to the unpleasant fishy aftertaste in the mouth remains an open problem. First, intensities of unpleasant fishy aftertaste of wine and dried scallop pairings were rated by sensory analysis.

Replacing the cyclohexene-linker of FR181157 leading to novel IP receptor agonists: orally active prostacyclin mimetics. Part 6.

The synthesis and biological activity of novel derivatives of our previously reported IP receptor agonist FR181157 is described. SAR studies to replace the cyclohexene-linker of FR181157 led to the discovery of compound 1i (FR207845) as a potent non-prostanoid PGI2 mimetic with good oral bioavailability.

Metabolism investigation leading to novel drug design 2: orally active prostacyclin mimetics. Part 5.

A metabolism study of FK788 (2) led to the discovery of new diphenylcarbamoyl derivatives as prostacyclin mimetics without the PG skeleton. We designed and evaluated PGI(2) mimetics based on blocking the main metabolic pathway of FK788. The new compound 7c was found to be equipotent to FK788 towards PGI(2) agonist activity and metabolically more stable than FK788.

Discovery of new diphenyloxazole derivatives containing a pyrrolidine ring: orally active prostacyclin mimetics. Part 2.

Synthetic and biological evaluation of novel diphenyloxazole derivatives containing a pyrrolidine ring, as a prostacyclin mimetic without the PG skeleton, are described. Asymmetric reduction of a ketone using a chiral Ru complex and reductive amination by NaBH(4) produces four isomers of the tetrahydronaphthalene ring and the pyrrolidine ring with high stereoselectivity. FR193262 (4), (R,R)-diphenyloxazolyl pyrrolidine derivative, displays high potency and agonist efficacy at the IP receptor and has good bioavailability in rats and dogs.

Metabolism investigation leading to novel drug design: orally active prostacyclin mimetics. Part 4.

A metabolism study of FR181157 (1) led to the discovery of new oxazole derivatives as active metabolites. The metabolite 6 with an epoxy ring exhibited high anti-aggregative potency with an IC(50) of 5.8 nM and potent binding affinity for the human recombinant IP receptor with a K(i) value of 6.

Discovery of diphenylcarbamate derivatives as highly potent and selective IP receptor agonists: orally active prostacyclin mimetics. Part 3.

The new classes of diphenylcarbamate derivatives with a tetrahydronaphthalene skeleton as highly potent and selective IP agonists have been discovered. The optimized diphenylcarbamate type compound FK-788: (R)-4 exhibited potent antiaggregative potency with an IC50 of 18 nM and high binding affinity for the human recombinant IP receptor with K(i) values of 20 nM and selectivity for human IP over all other members of the human prostanoid receptor family. Compound (R)-4 was shown to exhibit good pharmacokinetic properties in rats and dogs, and also good bioavailability in healthy volunteers.

A simple stereoselective synthesis and biological evaluation of FR181157: orally active prostacyclin mimetic.

Synthetic method of a novel prostaglandin (PG) mimetic: FR181175 without PG skeleton are described. The key to success is creation of a chiral epoxide using Sharpless AD reaction with high ee yield. FR181157 shows high potency and agonist efficacy at the IP receptor and has good bioavailability.