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ABSTRACT:The renal outer medullary potassium channel (ROMK or K ir 1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal highthroughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a potent ROMK inhibitor. It is worth noting that this compound was identified as a minor impurity in a screening hit that was responsible for all of the initially observed ROMK activity. Structure−activity studies resulted in analogues with improved rat pharmacokinetic properties and selectivity over the hERG channel, providing tool compounds that can be used for in vivo pharmacological assessment. The featured ROMK inhibitors were also selective against other members of the inward rectifier family of potassium channels.

An effective total synthesis of the marine sponge cytotoxin (+)-psymberin [irciniastatin (1)] has been achieved. Highlights of the strategy include a Diels-Alder reaction between a bissiloxy diene and an allene to construct the aromatic ring, a boron-mediated aldol to elaborate the C(15-17) all syn stereotriad, catalytic reagent control to set the C(8, 9, 11 and 13) stereogenic centers of the tetrahydropyran core, and a late-stage Curtius rearrangement to install the sensitive N,O-aminal moiety. The synthesis proceeds with a longest linear sequence of 21 steps from commercially a v a2,2i-diml ethayl-1b,3-plropaenediol.In 2004, the laboratories of Pettit and Crews independently disclosed the isolation of ircinistatin A 1 and psymberin (1), 2 respectively from the marine sponges Ircinia ramose and Psammocinia sp. A closely related compound, irciniastatin B, possessing a carbonyl moiety at C(11) was also reported by the Pettit group. From the outset, irciniastatin A and psymberin appeared to be constitutionally equivalent based on high resolution mass spectrometry, in conjunction with the 1D and 2D NMR data. The absolute configuration of psymberin was assigned by the Crews group based on a combination of CD studies along with the assumed analogy to the structure of pederin. 3 Neither group however assigned the relative stereogenecity at C(4); also recorded were conflicting stereochemical assignments for the C(8) N,O-aminal. Importantly, both isolates displayed significant cancer cell growth inhibitory activity against a wide variety of human cancer cell lines. The potent cytotoxicity data, in conjuction with the conflicting and smithab@sas.upenn.edu. Shortly thereafter, the DeBrabander group announced completion of the first total synthesis of (+)-psymberin, complete with construction of the four possible C(4)-C(8) epimers, which not only completed the structural assignment, including absolute configuration, but also confirmed that irciniastatin A and psymberin (1) were in fact one and the same. 5 Related synthetic work followed quickly, 6 with a formal synthesis in 2007 7 and a second total synthesis reported by the Schering-Plough group, 8 the latter exploiting a novel (diacetoxyiodo)benzene-mediated cyclization to construct the central tetrahydropyran core. NIH Public AccessWe also were intrigued with (+)-psymberin (1) as a potential new cancer therapeutic lead. Herein we report our efforts recently culminating in an effective total synthesis of (+)-1. Central to our synthetic plan was the use of catalytic reagent control to set the stage for an eventual structure-activity study to define the structural elements required for biological activity. 9With this overview in mind, disconnection of the amide bond in (+)-1 (Scheme 1), as with the earlier reported syntheses, 5,7,8 leads to a side chain acid (2) and amide coupling precursor (3), the latter bearing a Teoc-protected N,O-aminal. We envisioned that elaboration of the N,Oaminal could be achieved in a highly stereoselective fashion exploiting a late-stag...

ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK inhibitor clinical candidate, MK-7145.

A unified synthetic strategy to access (+)-irciniastatin A (a.k.a. psymberin) and (−)- irciniastatin B, two cytotoxic secondary metabolites, has been achieved. Highlights of the convergent strategy comprise a boron-mediated aldol union to set the C(15)–C(17) syn-syn triad, reagent control to set the four stereocenters of the tetrahydropyran core, and a late-stage Curtius rearrangement to install the acid-sensitive stereogenic N,O-aminal. Having achieved the total synthesis of (+)-irciniastatin A, we devised an improved synthetic route to the tetrahydropyran core (13 steps) compared to the first-generation synthesis (22 steps). Construction of the structurally similar (−)-irciniastatin B was then achieved via modification of a late-stage (−)-irciniastatin A intermediate to implement a chemoselective deprotection/oxidation sequence to access the requisite oxidation state at C(11) of the tetrahydropyran core. Of particular significance, the unified strategy will permit late-stage diversification for analogue development, designed to explore the biological role of substitution at the C(11) position of these highly potent tumor cell growth inhibitory molecules.

The lituarines A-C comprise an architecturally novel, biologically active family of marine natural products (1-3; Figure 1) reported by Vidal and co-workers in 1992. 1a Isolated from the sea pen Lituaria australasaie, endemic to the western region of the New Caledonian Lagoon near the Baie de St. Vincent, their structures, including the connectivities and relative stereochemistries, were assigned on the basis of multidimensional NMR techniques; 1b the absolute stereochemistry remains undefined. From the biomedical perspective, the lituarines display significant cytotoxicities toward KB cells [(1): IC 50 ) 5.5-7.5 nM; (2): IC 50 ) 1-3 nM; (3): IC 50 ) 7-9 nM]. Intrigued both by the architecture and the biological activities of the lituarines, we initiated a research program directed toward the total synthesis of the lituarines. 2,3 The Robertson laboratory has also reported progress in this area. 4

A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust pharmacodynamic effects in both SD rats and dogs have been demonstrated.

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