Publications by authors named "Simona Bindi"

11 Publications

  • Page 1 of 1

Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders.

Bioorg Med Chem 2015 May 28;23(10):2387-407. Epub 2015 Mar 28.

Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

Compound 1, a hit from the screening of our chemical collection displaying activity against JAK2, was deconstructed for SAR analysis into three regions, which were explored. A series of compounds was synthesized leading to the identification of the potent and orally bioavailable JAK2 inhibitor 16 (NMS-P830), which showed an encouraging tumour growth inhibition in SET-2 xenograft tumour model, with evidence for JAK2 pathway suppression demonstrated by in vivo pharmacodynamic effects.
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http://dx.doi.org/10.1016/j.bmc.2015.03.059DOI Listing
May 2015

Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors.

Bioorg Med Chem 2014 Sep 21;22(17):4998-5012. Epub 2014 Jun 21.

Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.
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http://dx.doi.org/10.1016/j.bmc.2014.06.025DOI Listing
September 2014

Discovery of NMS-E973 as novel, selective and potent inhibitor of heat shock protein 90 (Hsp90).

Bioorg Med Chem 2013 Nov 19;21(22):7047-63. Epub 2013 Sep 19.

Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano, MI, Italy. Electronic address:

Novel small molecule inhibitors of heat shock protein 90 (Hsp90) were discovered with the help of a fragment based drug discovery approach (FBDD) and subsequent optimization with a combination of structure guided design, parallel synthesis and application of medicinal chemistry principles. These efforts led to the identification of compound 18 (NMS-E973), which displayed significant efficacy in a human ovarian A2780 xenograft tumor model, with a mechanism of action confirmed in vivo by typical modulation of known Hsp90 client proteins, and with a favorable pharmacokinetic and safety profile.
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http://dx.doi.org/10.1016/j.bmc.2013.09.018DOI Listing
November 2013

Thieno[3,2-c]pyrazoles: a novel class of Aurora inhibitors with favorable antitumor activity.

Bioorg Med Chem 2010 Oct 25;18(19):7113-20. Epub 2010 Jul 25.

Nerviano Medical Sciences-Oncology, via Pasteur 10, 20014 Nerviano, Milan, Italy.

A novel series of 3-amino-1H-thieno[3,2-c]pyrazole derivatives demonstrating high potency in inhibiting Aurora kinases was developed. Here we describe the synthesis and a preliminary structure-activity relationship, which led to the discovery of a representative compound (38), which showed low nanomolar inhibitory activity in the anti-proliferation assay and was able to block the cell cycle in HCT-116 cell line. This compound demonstrated favorable pharmacokinetic properties and good efficacy in the HL-60 xenograft tumor model.
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http://dx.doi.org/10.1016/j.bmc.2010.07.048DOI Listing
October 2010

Optimization of pyrazole inhibitors of Coactivator Associated Arginine Methyltransferase 1 (CARM1).

Bioorg Med Chem Lett 2009 Jun 22;19(11):2924-7. Epub 2009 Apr 22.

Bristol-Myers Squibb Pharmaceutical Research and Development, Princeton, NJ 08543, United States.

Design, synthesis, and SAR development led to the identification of the potent, novel, and selective pyrazole based inhibitor (7f) of Coactivator Associated Arginine Methyltransferase (CARM1).
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http://dx.doi.org/10.1016/j.bmcl.2009.04.075DOI Listing
June 2009

1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile.

J Med Chem 2006 Nov;49(24):7247-51

Nerviano Medical Sciences S.r.l. viale Pasteur 10, 20014 Nerviano, Milan, Italy.

The optimization of a series of 5-phenylacetyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives toward the inhibition of Aurora kinases led to the identification of compound 9d. This is a potent inhibitor of Aurora kinases that also shows low nanomolar potency against additional anticancer kinase targets. Based on its high antiproliferative activity on different cancer cell lines, favorable chemico-physical and pharmacokinetic properties, and high efficacy in in vivo tumor models, compound 9d was ultimately selected for further development.
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http://dx.doi.org/10.1021/jm060897wDOI Listing
November 2006

Potent and selective Aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition.

J Med Chem 2005 Apr;48(8):3080-4

Nerviano Medical Sciences - Oncology, via Pasteur 10, 20014 Nerviano, Milan, Italy.

Potent and selective Aurora kinase inhibitors were identified from the combinatorial expansion of the 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole bi-cycle, a novel and versatile scaffold designed to target the ATP pocket of protein kinases. The most potent compound reported in this study had an IC(50) of 0.027 microM in the enzymatic assay for Aur-A inhibition and IC(50)s between 0.05 microM and 0.5 microM for the inhibition of proliferation of different tumor cell lines.
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http://dx.doi.org/10.1021/jm049076mDOI Listing
April 2005

A Concise beta-Lactam Route to Short Peptide Segments Containing beta,beta-Disubstituted beta-Amino Acids.

J Org Chem 1998 Apr;63(8):2469-2474

Departamento de Química Orgánica, Facultad de Química, Universidad del País Vasco, Apdo 1072, 20080 San Sebastián, Spain.

An efficient epimerization-free route toward beta,beta-disubstituted beta-amino acid-containing peptides is described. The methodology involves the use of 4,4-disubstituted-N-Boc beta-lactams as acylating agents, which upon coupling with amino acid esters, promoted by potassium cyanide, give rise to dipeptides with no appreciable racemization. By this procedure short peptide segments containing a four-, five-, or six-membered ring at the beta-position of the beta-amino acid residue have been prepared. The method has also proven to be valuable for the preparation of tripeptides. In addition the sterically hindered amino terminus of the beta-amino acid can undergo peptide couplings under standard conditions.
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http://dx.doi.org/10.1021/jo9712862DOI Listing
April 1998

A Selective Access to Amino Hydroxy Oxetanes.

J Org Chem 1997 Nov;62(24):8557-8559

Centro CNR Composti Eterociclici, Dipartimento di Chimica Organica "U. Schiff", via G. Capponi 9, I-50121 Firenze, Italy.

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http://dx.doi.org/10.1021/jo9708607DOI Listing
November 1997

A Selective and General Access to Trisubstituted Oxetanes.

J Org Chem 1996 Jun;61(13):4466-4468

Centro CNR Composti Eterociclici, Dipartimento di Chimica Organica "U. Schiff", via G. Capponi 9, I-50121 Firenze, Italy.

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http://dx.doi.org/10.1021/jo9604595DOI Listing
June 1996

Different Pathways in the Base-Promoted Isomerization of Benzyl Oxiranyl Ethers.

J Org Chem 1996 Jun;61(13):4374-4378

Centro CNR Composti Eterociclici, c/o Dipartimento di Chimica Organica "U. Schiff", via G. Capponi 9, 50121 Firenze, Italy.

The base-promoted isomerization of benzyl oxiranyl ethers was investigated. In particular it was shown that the reaction may proceed toward two main regioisomeric products: a benzyl vinyl ether or a 2-aryl-3-(hydroxyalkyl)oxetane, depending on subtle variations in the substitution on the phenyl ring. Disubstituted oxetanes were obtained in a stereoselective manner, thus providing a good entry to this class of synthetically useful compounds.
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http://dx.doi.org/10.1021/jo960226dDOI Listing
June 1996