Ernest Seiichi Hamanaka

Discovery of zoniporide: A potent and selective sodium–hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility

Zoniporide (CP-597,396) is a potent and selective inhibitor of NHE-1, which exhibits high aqueous solubility and acceptable pharmacokinetics for intravenous administration. The discovery, synthesis, activities, and rat and dog pharmacokinetics of this compound are presented. The potency and selectivity of zoniporide may be due to the conformation that the molecule adopts due to the presence of a cyclopropyl and a 5-quinolinyl substituent on the central pyrazole ring of the molecule.

Zoniporide: a potent and highly selective inhibitor of human Na(+)/H(+) exchanger-1.

We evaluated the in vitro pharmacological profile of a novel, potent and highly selective Na(+)/H(+) exchanger-1 (NHE-1) inhibitor, [1-(Quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine hydrochloride monohydrate (zoniporide or CP-597,396). The potency and selectivity of zoniporide were determined via inhibition of 22Na(+) uptake by PS-120 fibroblast cell lines overexpressing human NHE-1, -2 or rat NHE-3. Additionally, potency for endogenous NHE-1 was confirmed via ex vivo human platelet swelling assay (PSA), in which platelet swelling was induced by exposure to sodium propionate. The pharmacological profile of zoniporide was compared with that of eniporide and cariporide. Zoniporide inhibited 22Na(+) uptake in fibroblasts expressing human NHE-1 in a concentration-dependent manner (IC(50) = 14 nM) and was highly selective (157-fold and 15,700-fold vs. human NHE-2 and rat NHE-3, respectively). Zoniporide was 1.64- to 2.6-fold more potent at human NHE-1 than either eniporide or cariporide (IC(50) = 23 and 36 nM, respectively). Zoniporide was also more selective at inhibiting human NHE-1 vs. human NHE-2 than either eniporide or cariporide (157-fold selective compared with 27- and 49-fold, respectively). All three compounds inhibited human platelet swelling with IC(50) values in low nanomolar range. From these results, we conclude that zoniporide represents a novel, potent and highly selective NHE-1 inhibitor.

Stereoselective synthesis of 6β-substituted penicillanates

Abstract Reduction of 6-substituted-6-halopenicillanates with tri-n-butyltin hydride can produce stereoselectively 6β-substituted derivatives.

Modulators of dyslipidaemia

Coronary heart disease (CHD) is the leading cause of morbidity and mortality in most developed nations and atherosclerotic cardiovascular disease accounts for approximately one-half of all deaths due to CHD. Dyslipidaemias, which include various combinations of hypercholesterolaemia, hypertriglyceridaemia and hypoalphalipoproteinaemia, are major risk factors for atherosclerotic CHD. Current therapy largely treats hypercholesterolaemia, as reflected in the sales of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (HMGR-Is, statins) which account for a worldwide market share of 88%. The fibrates, which account for 9% of worldwide market share, effectively treat hypertriglyceridaemia but have inconsistent effects on hypercholesterolaemia and hypoalphalipoproteinaemia. Niacin, although an effective treatment for dyslipidaemias, suffers from a poor side-effect profile and therefore poor compliance. Moreover, niacin is not recommended for diabetics, a population in which atherosclerotic cardiovascular diseas...