ABSTRACT
A renal outer medullary potassium channel (ROMK, Kir1.1) is a putative drug target for a novel class of diuretics with potential for treating hypertension and heart failure. Our first disclosed clinical ROMK compound, 2 (MK-7145), demonstrated robust diuresis, natriuresis, and blood pressure lowering in preclinical models, with reduced urinary potassium excretion compared to the standard of care diuretics. However, 2 projected to a short human half-life (â¼5 h) that could necessitate more frequent than once a day dosing. In addition, a short half-life would confer a high peak-to-trough ratio which could evoke an excessive peak diuretic effect, a common liability associated with loop diuretics such as furosemide. This report describes the discovery of a new ROMK inhibitor 22e (MK-8153), with a longer projected human half-life (â¼14 h), which should lead to a reduced peak-to-trough ratio, potentially extrapolating to more extended and better tolerated diuretic effects.
Subject(s)
Natriuretic Agents/chemistry , Potassium Channel Blockers/chemistry , Potassium Channels, Inwardly Rectifying/antagonists & inhibitors , Action Potentials/drug effects , Animals , Benzofurans/chemistry , Blood Pressure/drug effects , Diuretics/chemistry , Diuretics/metabolism , Diuretics/pharmacology , Dogs , Half-Life , Haplorhini , Humans , Male , Natriuretic Agents/metabolism , Natriuretic Agents/pharmacology , Piperazines/chemistry , Potassium/urine , Potassium Channel Blockers/metabolism , Potassium Channel Blockers/pharmacology , Potassium Channels, Inwardly Rectifying/metabolism , Rats , Rats, Inbred SHRABSTRACT
The first chemical synthesis of pareitropone, by a route featuring application of alkynyliodonium salt chemistry, is described. The key transform initiates with addition of an alkylidenecarbene, derived by intramolecular nucleophile addition to the alkynyliodonium moiety, to a proximal aromatic ring. This addition delivers a highly strained norcaradiene substructure that rapidly reorganizes to furnish the pareitropone skeleton.
Subject(s)
Alkaloids/chemical synthesis , Antineoplastic Agents, Phytogenic/chemical synthesis , Isoquinolines/chemical synthesis , Methane/analogs & derivatives , Onium Compounds/chemistry , Combinatorial Chemistry Techniques , Hydrocarbons , Methane/chemistry , Molecular StructureABSTRACT
The synthesis of the tropoloisoquinoline alkaloid pareitropone has been accomplished in 14 steps from 2,3,4-trimethoxybenzoic acid. The key transformations include the generation of an alkylidenecarbene intermediate through intramolecular addition of a tosylamide anion to an alkynyliodonium salt, and the cycloaddition of that carbene to a peri positioned aromatic ring to afford a cycloheptatrienylidene product featuring the intact pareitropone skeleton.
Subject(s)
Alkaloids/chemical synthesis , Isoquinolines/chemical synthesis , Methane/analogs & derivatives , Onium Compounds/chemistry , Antineoplastic Agents, Phytogenic/chemical synthesis , Hydrocarbons , Methane/chemistryABSTRACT
The stereochemistry of the condensations of 2-cyclohexenones, alpha-arylidenecyclohexanones, and alpha-(tert-butyldimethylsiloxy)cyclohexanones carrying one or two (both syn and anti) spirotetrahydrofuran units adjacent to the carbonyl with allyl organometallics (especially indium) and with the Normant reagent (ClMgO(CH(2))(3)MgCl) is described. Good levels of anti stereoselection are observed in the alpha-arylidene series. Subsequent cyclization generates a second (or third) tetrahydrofuran ring possessing trans vicinal oxygens. Useful levels of matched and mismatched diastereoselection are also attainable by prior alpha-oxygenation. The intrinsic differences in diastereomer production between indium and magnesium organometallics are highlighted. A clear distinction regarding the anticipated direction of stereoselectivity is made on the grounds of chelation capabilities and the intra- or intermolecularity of carbon-carbon bond formation. Finally, the two protocols that are described in detail are shown to be iterative, a feature that augurs well for ultimately accessing the eight possible hexaspirocyclohexanes in an efficient and stereocontrolled manner.
