Publications by authors named "Barbara Pio"

14 Publications

  • Page 1 of 1

Discovery of MK-8153, a Potent and Selective ROMK Inhibitor and Novel Diuretic/Natriuretic.

J Med Chem 2021 06 26;64(11):7691-7701. Epub 2021 May 26.

Discovery Chemistry, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.

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, (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, projected to a short human half-life (∼5 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 (MK-8153), with a longer projected human half-life (∼14 h), which should lead to a reduced peak-to-trough ratio, potentially extrapolating to more extended and better tolerated diuretic effects.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00406DOI Listing
June 2021

Design, synthesis and biological evaluation of indane derived GPR40 agoPAMs.

Bioorg Med Chem Lett 2019 07 2;29(14):1842-1848. Epub 2019 May 2.

Discovery Chemistry, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.

GPR40 (FFAR1 or FFA1) is a G protein-coupled receptor, primarily expressed in pancreatic islet β-cells and intestinal enteroendocrine cells. When activated by fatty acids, GPR40 elicits increased insulin secretion from islet β-cells only in the presence of elevated glucose levels. Towards this end, studies were undertaken towards discovering a novel GPR40 Agonist whose mode of action is via Positive Allosteric Modulation of the GPR40 receptor (AgoPAM). Efforts were made to identify a suitable GPR40 AgoPAM tool molecule to investigate mechanism of action and de-risk liver toxicity of GPR40 AgoPAMs due to reactive acyl-glucuronide (AG) metabolites.
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http://dx.doi.org/10.1016/j.bmcl.2019.04.050DOI Listing
July 2019

Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40.

Nat Struct Mol Biol 2017 Jul 5;24(7):570-577. Epub 2017 Jun 5.

Department of Screening and Protein Science, Merck Research Laboratories, West Point, Pennsylvania, USA.

Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40-MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.
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http://dx.doi.org/10.1038/nsmb.3417DOI Listing
July 2017

The design and synthesis of novel spirocyclic heterocyclic sulfone ROMK inhibitors as diuretics.

Bioorg Med Chem Lett 2017 02 13;27(4):1109-1114. Epub 2016 Oct 13.

Department of Medicinal Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033, United States.

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.
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http://dx.doi.org/10.1016/j.bmcl.2016.10.032DOI Listing
February 2017

Discovery of a potent and selective ROMK inhibitor with improved pharmacokinetic properties based on an octahydropyrazino[2,1-c][1,4]oxazine scaffold.

Bioorg Med Chem Lett 2016 12 24;26(23):5695-5702. Epub 2016 Oct 24.

Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.

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.
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http://dx.doi.org/10.1016/j.bmcl.2016.10.064DOI Listing
December 2016

Improved Stability of Proline-Derived Direct Thrombin Inhibitors through Hydroxyl to Heterocycle Replacement.

ACS Med Chem Lett 2015 May 13;6(5):553-7. Epub 2015 Mar 13.

Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.

Modification of the previously disclosed (S)-N-(2-(aminomethyl)-5-chlorobenzyl)-1-((R)-2-hydroxy-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide 2 by optimization of the P3 group afforded novel, low molecular weight thrombin inhibitors. Heterocycle replacement of the hydroxyl functional group helped maintain thrombin in vitro potency while improving the chemical stability and pharmacokinetic profile. These modifications led to the identification of compound 10, which showed excellent selectivity over related serine proteases as well as in vivo efficacy in the rat arteriovenous shunt. Compound 10 exhibited significantly improved chemical stability and pharmacokinetic properties over 2 and may be utilized as a structurally differentiated preclinical tool comparator to dabigatran etexilate (Pro-1) to interrogate the on- and off-target effects of oral direct thrombin inhibitors.
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http://dx.doi.org/10.1021/acsmedchemlett.5b00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434479PMC
May 2015

Pyrazole-based cathepsin S inhibitors with improved cellular potency.

Bioorg Med Chem Lett 2007 Oct 22;17(20):5525-8. Epub 2007 Aug 22.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

High potency pyrazole-based noncovalent inhibitors of human cathepsin S (CatS) were developed by modification of the benzo-fused 5-membered ring heterocycles found in earlier series of CatS inhibitors. Although substitutions on this heterocyclic framework had a moderate impact on enzymatic potency, dramatic effects on cellular activity were observed. Optimization afforded indole- and benzothiophene-derived analogues that were high affinity CatS inhibitors (IC(50)=20-40 nM) with good cellular potency (IC(50)=30-340 nM).
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http://dx.doi.org/10.1016/j.bmcl.2007.08.038DOI Listing
October 2007

Dihydro-[1H]-quinolin-2-ones as retinoid X receptor (RXR) agonists for potential treatment of dyslipidemia.

Bioorg Med Chem Lett 2007 Jun 25;17(12):3491-6. Epub 2007 Jan 25.

Johnson and Johnson Pharmaceutical Research and Development, Cranbury, NJ 08512, USA.

A number of RXR modulators with novel structural features were synthesized and screened in the functional assays. The synthesis and the structure-activity relationship within the series of compounds will be presented. Some in vivo data generated in the models for dyslipidemia and diabetes will also be presented.
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http://dx.doi.org/10.1016/j.bmcl.2007.01.049DOI Listing
June 2007

RXR-LXR heterodimer modulators for the potential treatment of dyslipidemia.

Bioorg Med Chem Lett 2007 Jun 24;17(12):3497-503. Epub 2007 Jan 24.

Johnson and Johnson Pharmaceutical Research and Development, Cranbury, NJ 08869, USA.

A number of RXR agonists were synthesized and screened in functional assays. The synthesis and the structure-activity relationship (SAR) within the series of compounds will be presented. Some in vivo data in rodent models for dyslipidemia and diabetes will also be presented.
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http://dx.doi.org/10.1016/j.bmcl.2007.01.047DOI Listing
June 2007

Discovery of an androgen receptor modulator pharmacophore based on 2-quinolinones.

Bioorg Med Chem Lett 2007 Mar 13;17(6):1523-6. Epub 2007 Jan 13.

Discovery Research, Ligand Pharmaceuticals, 10275 Science Center Drive, San Diego, CA 92121, USA.

A series of alkylamino-2-quinolinone compounds (3) was discovered as androgen receptor modulators based on an early linear tricyclic quinoline pharmacophore (1). The series demonstrated selective high binding affinity to androgen receptor and potent receptor modulating activities in the cotransfection assays.
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http://dx.doi.org/10.1016/j.bmcl.2007.01.007DOI Listing
March 2007

Preparation and biological evaluation of indole, benzimidazole, and thienopyrrole piperazine carboxamides: potent human histamine h(4) antagonists.

J Med Chem 2005 Dec;48(26):8289-98

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [(3)H]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H(4) antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.
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http://dx.doi.org/10.1021/jm0502081DOI Listing
December 2005

5-benzylidene-1,2-dihydrochromeno[3,4-f]quinolines as selective progesterone receptor modulators.

J Med Chem 2003 Sep;46(19):4104-12

Discovery Research, Ligand Pharmaceuticals Inc., 10275 Science Center Drive, San Diego, California 92121, USA.

A series of 5-benylidene-1,2-dihydrochromeno[3,4-f]quinolines (4) were synthesized and tested in bioassays to evaluate their progestational activities, receptor- and tissue-selectivity profiles as selective progesterone receptor modulators (SPRMs). Most of the new analogues exhibited as highly potent progestins with more than 100-fold receptor selectivity over other steroid hormone receptors and LG120920 (7b) demonstrated tissue selectivity toward uterus and vagina versus breasts in a rodent model after oral administration.
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http://dx.doi.org/10.1021/jm020477gDOI Listing
September 2003

Development of progesterone receptor antagonists from 1,2-dihydrochromeno[3,4-f]quinoline agonist pharmacophore.

Bioorg Med Chem Lett 2003 Jun;13(12):2075-8

Discovery Research, Ligand Pharmaceuticals, 10275 Science Center Drive, San Diego, CA 92121, USA.

A series of 1,2-dihydrochromeno[3,4-f]quinoline derivatives was synthesized and tested in biological assays to evaluate the nonsteroidal progesterone receptor modulator pharmacophore (4) as antiprogestins. A number of potent analogues were identified by modification of the substituents at the D-ring.
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http://dx.doi.org/10.1016/s0960-894x(03)00256-7DOI Listing
June 2003

Synthesis and biological activity of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives as progesterone receptor modulators.

Bioorg Med Chem Lett 2003 Jun;13(12):2071-4

Discovery Research, Ligand Pharmaceuticals, 10275 Science Center Drive, San Diego, CA 92121, USA.

A series of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives were synthesized and tested in biological assays to evaluate scope and limitations of the nonsteroidal SPRM pharmacophore (3). A number of orally available highly potent nonsteroidal modulators were identified by modification of the substituents at 5-methylidene position.
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http://dx.doi.org/10.1016/s0960-894x(03)00255-5DOI Listing
June 2003