Yasuhiko Kanda

Synthesis and structure–activity relationships of potent and orally active sulfonamide ETB selective antagonists

The synthesis and structure activity relationships of a series of N-pyrimidinyl benzenesulfonamides as ETB selective antagonists are described. N-Isoxazolyl benzenesulfonamide 1a, previously reported, (1) was selected as a lead compound, and isosteric replacement of the isoxazole ring of 1a with a pyrimidine ring led to the discovery of the highly potent ETB selective antagonist 6e with oral bioavailability. Modification of the terminal aldehyde group at the 6-position of the pyrimidine ring was investigated, and malonate 15b and acylhydrazone 16f were found to be equipotent to aldehyde 6e. Compound 6e showed ETB antagonistic activity on in vivo evaluation.

A novel allylic hydroxylation of sterically hindered olefins by Fe-porphyrin-catalyzed mCPBA oxidation

A novel allylic hydroxylation by mCPBA of triterpenes bearing sterically hindered olefin is catalyzed by Fe(PFPP)Cl. Oleanolic acid, ursolic acid, dihydrolanosterol and their derivatives are converted to the corresponding allylic alcohols by mCPBAFe(PFPP)Cl under mild conditions. In contrast, for common or electron-deficient olefins, mCPBAFe(PFPP)Cl is an efficient epoxidation system. The intermediacy of an Fe-oxo-porphyrin and subsequent hydrogen abstraction and recombination are proposed for the selective α-hydroxylation of triterpenes.

Synthesis and pharmacological properties of ureidomethylcarbamoylphenylketone derivatives. A new potent and subtype-selective nonpeptide CCK-B/gastrin receptor antagonist, S-0509.

A novel series of CCK-B/gastrin receptor antagonists-ureidomethylcarbamoylphenylketone derivatives-were designed, synthesized, and evaluated for activity. Structure-activity relationship studies revealed the importance of a carboxylic acid at substituent R2 and tert-butoxycarbonyl group at R1 in structure A. Compound 7a (S-0509) showed remarkable affinity for the CCK-B/gastrin receptor and a subtype selectivity profile in vitro. Administration (id) of 7a led to excellent inhibition of gastric acid secretion induced by pentagastrin in anesthetized rats with an ED50 value of 0.014 mg/kg. Furthermore, 7a proved to have poor blood-brain permeability by its small effect on enhancement of morphine analgesia. Thus, S-0509 has an increase in selectivity for the peripheral effects of gastrin antagonism from the central effects of CCK-B antagonism.

SYNTHESIS OF 2-13C-OLEANOLIC ACID AND 2-13C-MYRICERONE

Abstract Synthetic way for 13C-labeled oleanolic acid 1 and myricerone 2 has been developed, starting from the parent 1 and 2. The procedure involves ring opening and closure of the A rings of these oleanane triterpenes. 13C was introduced into the 2-position by 13C-MeLi as an isotope source. Chelation controlled addition of methyllithium to α-hydoxypentanone 11 is a common crucial step for labeling of 1 and 2, and judicious choice of protecting groups is essential for 2.

Directed lithiation of N-(tert-butoxycarbonyl)aminoisoxazole: synthesis of 4-substituted aminoisoxazoles

Abstract Directed lithiation of 3-(Boc-amino)isoxazole 4 and 5-(Boc-amino)isoxazole 9 is described. Dilithioisoxazoles reacted with a variety of electrophiles to give the corresponding 4-substituted isoxazoles.

Enol glycosylation at α,β-unsaturated ketone on glycyrrhetic acid derivatives

Abstract Glycyrrhetic acid derivatives having no OH and slightly reactive OH groups with methyl 2,3,4-tri- O -acetyl-α-D-glucuronatopyranosyl bromide ( 3 ) in the presence of AgOTf or Hg(CN) 2 and HgBr 2 in CH 2 Cl 2 gave enol α-D-glycosides.

Discovery and synthesis of a potent sulfonamide ETB selective antagonist

The synthesis and structure activity relationships of a series of sulfonamide endothelin antagonists are described. In the course of our modification studies, we discovered ET(B) selective antagonists. The most potent compound 15f displays IC50 values of 1.7 microM and 0.002 microM to ET(A) and ET(B) receptors, respectively.