Kohji Fukatsu

Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist.

Ramelteon (TAK-375) is a novel melatonin receptor agonist currently under investigation for the treatment of insomnia. This study describes the neurochemical and receptor binding characteristics of ramelteon in vitro. Ramelteon showed very high affinity for human MT1 (Mel1a) and MT2 (Mel1b) receptors (expressed in Chinese hamster ovary [CHO] cells), and chick forebrain melatonin receptors (consisting of Mel1a and Mel1c receptors) with Ki values of 14.0, 112, and 23.1 pM, respectively, making the affinities of ramelteon for these receptors 3-16 times higher than those of melatonin. The affinity of ramelteon for hamster brain MT3 binding sites was extremely weak (Ki: 2.65 microM) compared to melatonins affinity for the MT3 binding site (Ki: 24.1 nM). In addition, ramelteon showed no measurable affinity for a large number of ligand binding sites (including benzodiazepine receptors, dopamine receptors, opiate receptors, ion channels, and transporters) and no effect on the activity of various enzymes. Ramelteon inhibited forskolin-stimulated cAMP production in the CHO cells that express the human MT1 or MT2 receptors. Taken together, these results indicate that ramelteon is a potent and highly selective agonist of MT1/MT2 melatonin receptors.

Design, synthesis, and structure–activity relationships of novel spiro-piperidines as acetyl-CoA carboxylase inhibitors

Spiro-lactone (S)-1 is a potent acetyl-CoA carboxylase (ACC) inhibitor and was found to be metabolically liable in human hepatic microsomes. To remove one of the risk factors in human study by improving the metabolic stability, we focused on modifying the spiro-lactone ring and the benzothiophene portion of the molecule. Spiro-imide derivative 8c containing a 6-methylthieno[2,3-b]pyridine core exhibited potent ACC inhibitory activity and favorable pharmacokinetic profiles in rats.

Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoA carboxylase inhibitors.

Spiro-pyrazolidinedione derivatives without quaternary chiral center were discovered by structure-based drug design and characterized as potent acetyl-CoA carboxylase (ACC) inhibitors. The high metabolic stability of the spiro-pyrazolo[1,2-a]pyridazine scaffold and enhancement of the activity by incorporation of a 7-methoxy group on the benzothiophene core successfully led to the identification of compound 4c as an orally bioavailable and highly potent ACC inhibitor. Oral administration of 4c significantly decreased the values of the respiratory quotient in rats, indicating the stimulation of fatty acid oxidation.

Design, synthesis, and structure-activity relationships of spirolactones bearing 2-ureidobenzothiophene as acetyl-CoA carboxylases inhibitors.

The co-crystal structure of the human acetyl-coenzyme A 2 (ACC2) carboxyl transferase domain and the reported compound CP-640186 (1b) suggested that two carbonyl groups are essential for potent ACC2 inhibition. By focusing on enhancing the interactions between the two carbonyl groups and the amino acid residues Gly(2162) and Glu(2230), we used ligand- and structure-based drug design to discover spirolactones bearing a 2-ureidobenzothiophene moiety.

Synthesis of TAK-218 using (R)-2-methylglycidyl tosylate as a chiral building block

Abstract We performed an asymmetric synthesis of ( S )-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)methyl]-5-benzofuranamine dihydrochloride (TAK-218, 1 ), a compound used for the treatment of traumatic and ischemic central nervous system injuries. Oxirane 6 , which was synthesized from ( R )-2-methylglycidyl tosylate, was treated with aqueous trifluoroacetic acid to afford benzofuranmethanol 7 with inversion of stereochemistry at the stereogenic center. Compound 7 was converted into 1 with high enantiomeric excess in four steps.

Kinetic Resolutions of Indan Derivatives Using Bacteria

Racemic indan derivatives have been resolved by the hydrolysis of amide bonds using Corynebacterium ammoniagenes IFO12612 to produce (S)-amine and (R)-amides. In the kinetic resolution of 1 (N-[2-(6-methoxy-indan-1-yl)ethyl]acetamide), it was possible to run the reaction to 44% conversion on a 10-g scale, obtaining (S)-amine 4 ((S)-2-(6-methoxy-indan-1-yl)ethylamine) at >99% enantiomeric excess (ee) and (R)-1 at 98% ee.