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1.
Bioorg Med Chem Lett ; 27(4): 1109-1114, 2017 02 15.
Article in English | MEDLINE | ID: mdl-28111141

ABSTRACT

A spirocyclic class of ROMK inhibitors was developed containing a structurally diverse heterocyclic sulfone moiety and spirocyclic core starting from lead 1. These compounds not only displayed exquisite ROMK potency but significantly improved selectivity over hERG. The lead compounds were found to have favorable pharmacokinetic properties and displayed robust diuretic, natriuretic and blood pressure lowering effects in spontaneously hypertensive rats.


Subject(s)
Diuretics/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Potassium Channels, Inwardly Rectifying/antagonists & inhibitors , Sulfones/pharmacology , Animals , Heterocyclic Compounds/chemical synthesis , Rats , Rats, Inbred SHR
2.
Bioorg Med Chem Lett ; 26(23): 5695-5702, 2016 12 01.
Article in English | MEDLINE | ID: mdl-27839686

ABSTRACT

Following the discovery of small molecule acyl piperazine ROMK inhibitors, the acyl octahydropyrazino[2,1-c][1,4]oxazine series was identified. This series displays improved ROMK/hERG selectivity, and as a consequence, the resulting ROMK inhibitors do not evoke QTc prolongation in an in vivo cardiovascular dog model. Further efforts in this series led to the discovery of analogs with improved pharmacokinetic profiles. This new series also retained comparable ROMK potency compared to earlier leads.


Subject(s)
Oxazines/chemistry , Oxazines/pharmacology , Potassium Channels, Inwardly Rectifying/antagonists & inhibitors , Animals , Diuresis/drug effects , Dogs , Heart Failure/drug therapy , Humans , Hypertension/drug therapy , Macaca mulatta , Oxazines/pharmacokinetics , Potassium Channels, Inwardly Rectifying/metabolism , Rats, Sprague-Dawley , Transcriptional Regulator ERG/antagonists & inhibitors , Transcriptional Regulator ERG/metabolism
3.
ACS Med Chem Lett ; 7(7): 697-701, 2016 Jul 14.
Article in English | MEDLINE | ID: mdl-27437080

ABSTRACT

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.

4.
Bioorg Med Chem Lett ; 26(9): 2339-43, 2016 May 01.
Article in English | MEDLINE | ID: mdl-27017115

ABSTRACT

Following the discovery of small molecule acyl piperazine ROMK inhibitors and their initial preclinical validation as a novel diuretic agent, our group set out to discover new ROMK inhibitors with reduced risk for QT effects, suitable for further pharmacological experiments in additional species. Several strategies for decreasing hERG affinity while maintaining ROMK inhibition were investigated and are described herein. The most promising candidate, derived from the newly discovered 4-N-heteroaryl acetyl series, improved functional hERG/ROMK ratio by >10× over the previous lead. In vivo evaluation demonstrated comparable diuretic effects in rat with no detectable QT effects at the doses evaluated in an in vivo dog model.


Subject(s)
ERG1 Potassium Channel/physiology , Heterocyclic Compounds/pharmacology , Piperazines/pharmacology , Heterocyclic Compounds/chemistry , Piperazines/chemistry , Structure-Activity Relationship
5.
ACS Med Chem Lett ; 6(7): 747-52, 2015 Jul 09.
Article in English | MEDLINE | ID: mdl-26191360

ABSTRACT

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.

6.
ACS Med Chem Lett ; 3(5): 367-72, 2012 May 10.
Article in English | MEDLINE | ID: mdl-24900480

ABSTRACT

The renal outer medullary potassium channel (ROMK or Kir1.1) 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 high-throughput 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.

7.
J Org Chem ; 72(23): 8976-9, 2007 Nov 09.
Article in English | MEDLINE | ID: mdl-17939719

ABSTRACT

Branched mannopentaoses were synthesized through two routes. While assembly from the nonreducing end to the reducing end was more convergent with fewer intermediate steps, two diastereomers were obtained. On the other hand, synthesis from the reducing end to the nonreducing end yielded the mannopentaose with the desired stereochemistry as a single isomer. Our results suggest that it is still challenging to reliably predict stereochemical outcome of a glycosylation reaction. It is necessary to thoroughly characterize anomeric configurations of newly formed glycosidic linkages in complex oligosaccharide synthesis.


Subject(s)
Mannose/chemistry , Oligosaccharides/chemical synthesis , Carbohydrate Conformation , Carbohydrate Sequence , Glycosylation , Molecular Sequence Data , Oligosaccharides/chemistry , Stereoisomerism
8.
Chemistry ; 12(20): 5246-52, 2006 Jul 05.
Article in English | MEDLINE | ID: mdl-16637084

ABSTRACT

A convenient two-step, one-pot procedure was developed for the conversion of primary alcohols to carboxylic acids. The alcohol was first treated with NaOCl and TEMPO under phase-transfer conditions, followed by NaClO2 oxidation in one pot. This reaction is applicable to a wide range of alcohols and the mild reaction conditions are compatible with many sensitive functional groups, including electron-rich aromatic rings, acid-labile isopropylidene ketal and glycosidic linkages, and oxidation-prone thioacetal, p-methoxybenzyl, and allyl moieties. Several glycosaminoglycans such as heparin, chondroitin, and hyaluronic acid oligosaccharides have been synthesized in high yields by using this new oxidation protocol.


Subject(s)
Alcohols/chemistry , Carboxylic Acids/chemical synthesis , Glycosaminoglycans/chemical synthesis , Antioxidants/chemistry , Benzyl Compounds/chemical synthesis , Carbohydrate Sequence , Catalysis , Cyclic N-Oxides/chemistry , Magnetic Resonance Spectroscopy , Molecular Sequence Data , Oligosaccharides/chemistry , Oxidation-Reduction , Perchlorates/chemistry , Spectrometry, Mass, Electrospray Ionization
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