Takashi Hayama

Aminophosphonate endothelin converting enzyme inhibitors : potency-enhancing and selectivity-improving modifications of phosphoramidon

Abstract A series of α-aminophosphonic acid derivatives and a series of phosphoramidate derivatives have been synthesized and evaluated as inhibitors of a phosphoramidon-sensitive metalloproteinase endothelin converting enzyme (ECE). Some of these compounds exhibit potent ECE inhibitory activity. The most potent inhibitor (XIIb) is about 10 times as potent as phosphoramidon.

A convenient synthetic method of a 5,7-diarylcyclopenteno[1,2-b]pyridine-6-carboxylate: A key intermediate for potent endothelin receptor antagonists

A convenient method for the synthesis of the title intermediate 4 was described. The key steps of this synthesis involved: (1) regioselective addition reaction of arylzinc reagent to quinolic anhydride in 42% isolated yield, (2) conversion of a ketoacid to an enone, which was achieved in 65% yield by intramolecular Knoevenagel reaction of beta-ketoester generated by condensation of an acid imidazolide with an ester enolate, followed by dehydration assisted with silica gel, and (3) stereoselective reduction of an allyl alcohol in 75% yield with zinc under acidic conditions. This synthesis enabled us to provide hundreds of grams of without chromatographic purification.

Marked reduction of mortality in salt-loaded Dahl salt-sensitive rats by the new, selective endothelin ETA receptor antagonist, J-105859.

Objective To examine the chronic effects of a newly synthesized, potent and selective endothelin (ET) ETA receptor antagonist, J-105859, on mortality in salt-loaded Dahl salt-sensitive (DS) rats and to conFIrm the potential of this compound as an ETA antagonist. Methods Vehicle and J-105859 were administered to saltloaded DS rats for 12 weeks. Throughout the experimental period, blood pressure was measured continuously using a telemetry system and the survival rate was determined. The surviving animals were subsequently sacrificed and autopsy was performed. Binding and functional assays were also carried out to characterize J-105859. Results The Ki values of J-105859 for cloned human ETA and ETB were 0.025 and 48 nmol/l, respectively. J-105859 inhibited ET-1-induced contractions in rabbit iliac artery (pA2 = 10.08) and BQ-3020 (ETB agonist)-induced contractions in pulmonary artery (pA2 = 7.63). The pressor response to intravenous (i.v.) ET-1 (0.5 nmol/kg) was significantly inhibited by J-105859 at a dose of 0.03 mg/kg i.v. Chronic treatment with J-105859 [0.1 and 1 mg/kg per day orally (p.o.)] from the prehypertensive stage decreased the mortality of salt-loaded DS rats and markedly inhibited the development of brain lesions. The survival rates in the control and J-105859 (0.1 and 1 mg/kg per day) groups were 34, 80 and 100%, respectively. Development of hypertension was markedly inhibited at a dose of 1 mg/kg per day. Conclusion J-105859 is a selective, potent, orally active ETA-selective antagonist. ETA antagonists may reduce morbidity as well as mortality in salt-sensitive hypertension.

6-Carboxy-5,7-diarylcyclopenteno[1,2-b]pyridine derivatives: a novel class of endothelin receptor antagonists.

Compounds (2-5) with a 6-carboxy-5,7-diarylcyclopentenopyridine skeleton were designed, synthesized, and identified as a new class of potent non-peptide endothelin receptor antagonists. The regio-isomer 2 was found to show potent inhibitory activity with an IC(50) value of 2.4 nM against (125)I-labeled ET-1 binding to human ET(A) receptors and a 170-fold selectivity for ET(A) over ET(B) receptors. Furthermore, 2 displayed more potent in vivo activity than did the indan-type compound 1 in a mouse ET-1 induced lethality model, suggesting the potential of 2 as a new lead structure. Derivatization on substituted phenyl groups at the 5- and 7-positions of 2 revealed that a 3,4-methylenedioxyphenyl group at the 5-position and a 4-methoxyphenyl group at the 7-position were optimal for binding affinity. Further derivatization of 2 by incorporating a substituent into the 2-position of the 4-methoxyphenyl group led to the identification of a more potent ET(A) selective antagonist 2p with an IC(50) value of 0.87 nM for ET(A) receptors and a 470-fold selectivity. In addition, 2p showed highly potent in vivo efficacy (AD(50): 0.04 mg/kg) in the lethality model.

Linear peptide ETA antagonists: rational design and practical derivatization of N-terminal amino- and imino-carbonylated tripeptide derivatives☆

Abstract Novel linear tripeptides possessing high endothelin antagonist activity were derived from endothelin antagonistic cyclic pentapeptides represented by BQ-123. The N-terminal urea moiety of the linear tripeptide derivatives was essential to show the strong antagonist activity. An easy method to prepare these peptides by treatment of the corresponding N-phenoxycarbonylated tripeptide esters with primary or secondary amines is described.