Publications by authors named "Claudio Fiorelli"

9 Publications

  • Page 1 of 1

Kernel-Based, Partial Least Squares Quantitative Structure-Retention Relationship Model for UPLC Retention Time Prediction: A Useful Tool for Metabolite Identification.

Anal Chem 2016 10 14;88(19):9510-9517. Epub 2016 Sep 14.

Drug Discovery and Development Department, Fondazione Istituto Italiano di Tecnologia , Via Morego 30, 16163 Genova, Italy.

We propose a new QSRR model based on a Kernel-based partial least-squares method for predicting UPLC retention times in reversed phase mode. The model was built using a combination of classical (physicochemical and topological) and nonclassical (fingerprints) molecular descriptors of 1383 compounds, encompassing different chemical classes and structures and their accurately measured retention time values. Following a random splitting of the data set into a training and a test set, we tested the ability of the model to predict the retention time of all the compounds. The best predicted/experimental R value was higher than 0.86, while the best Q value we observed was close to 0.84. A comparison of our model with traditional and simpler MLR and PLS regression models shows that KPLS better performs in term of correlation (R), prediction (Q), and support to MetID peak assignment. The KPLS model succeeded in two real-life MetID tasks by correctly predicting elution order of Phase I metabolites, including isomeric monohydroxylated compounds. We also show in this paper that the model's predictive power can be extended to different gradient profiles, by simple mathematical extrapolation using a known equation, thus offering very broad flexibility. Moreover, the current study includes a deep investigation of different types of chemical descriptors used to build the structure-retention relationship.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.analchem.6b02075DOI Listing
October 2016

Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor.

J Med Chem 2016 Apr 30;59(7):3392-408. Epub 2016 Mar 30.

Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.6b00064DOI Listing
April 2016

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2013.09.018DOI Listing
November 2013

Synthesis and structure-activity relationship (SAR) of 2-methyl-4-oxo-3-oxetanylcarbamic acid esters, a class of potent N-acylethanolamine acid amidase (NAAA) inhibitors.

J Med Chem 2013 Sep 30;56(17):6917-34. Epub 2013 Aug 30.

Drug Discovery and Development, Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.

N-Acylethanolamine acid amidase (NAAA) is a lysosomal cysteine hydrolase involved in the degradation of saturated and monounsaturated fatty acid ethanolamides (FAEs), a family of endogenous lipid agonists of peroxisome proliferator-activated receptor-α, which include oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). The β-lactone derivatives (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide (2) and (S)-N-(2-oxo-3-oxetanyl)-biphenyl-4-carboxamide (3) inhibit NAAA, prevent FAE hydrolysis in activated inflammatory cells, and reduce tissue reactions to pro-inflammatory stimuli. Recently, our group disclosed ARN077 (4), a potent NAAA inhibitor that is active in vivo by topical administration in rodent models of hyperalgesia and allodynia. In the present study, we investigated the structure-activity relationship (SAR) of threonine-derived β-lactone analogues of compound 4. The main results of this work were an enhancement of the inhibitory potency of β-lactone carbamate derivatives for NAAA and the identification of (4-phenylphenyl)-methyl-N-[(2S,3R)-2-methyl-4-oxo-oxetan-3-yl]carbamate (14q) as the first single-digit nanomolar inhibitor of intracellular NAAA activity (IC50 = 7 nM on both rat NAAA and human NAAA).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm400739uDOI Listing
September 2013

Synthesis and structure-activity relationship studies of O-biphenyl-3-yl carbamates as peripherally restricted fatty acid amide hydrolase inhibitors.

J Med Chem 2013 Jul 3;56(14):5917-30. Epub 2013 Jul 3.

Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia , via Morego 30, I-16163 Genova, Italy.

The peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor URB937 (3, cyclohexylcarbamic acid 3'-carbamoyl-6-hydroxybiphenyl-3-yl ester) is extruded from the brain and spinal cord by the Abcg2 efflux transporter. Despite its inability to enter the central nervous system (CNS), 3 exerts profound antinociceptive effects in mice and rats, which result from the inhibition of FAAH in peripheral tissues and the consequent enhancement of anandamide signaling at CB1 cannabinoid receptors localized on sensory nerve endings. In the present study, we examined the structure-activity relationships (SAR) for the biphenyl region of compound 3, focusing on the carbamoyl and hydroxyl groups in the distal and proximal phenyl rings. Our SAR studies generated a new series of peripherally restricted FAAH inhibitors and identified compound 35 (cyclohexylcarbamic acid 3'-carbamoyl-5-hydroxybiphenyl-3-yl ester) as the most potent brain-impermeant FAAH inhibitor disclosed to date.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm4007017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062305PMC
July 2013

Structure-based optimization of potent PDK1 inhibitors.

Bioorg Med Chem Lett 2010 Jul 8;20(14):4095-9. Epub 2010 Jun 8.

Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, Milano, Italy.

In this Letter is described the structure-based design of potent dihydro-pyrazoloquinazolines as PDK1 inhibitors. Starting from low potency HTS hits with the aid of X-ray crystallography and modeling, a medicinal chemistry activity was carried out to improve potency versus PDK1 and selectivity versus CDK2 protein kinase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2010.05.070DOI Listing
July 2010

Asymmetric synthesis of delta-substituted alpha,beta-unsaturated delta-lactams by ring closing metathesis of enantiomerically pure N-acryloyl-homoallylic amines.

J Org Chem 2007 Aug 11;72(16):6022-8. Epub 2007 Jul 11.

Dipartimento di Chimica G. Ciamician, Università di Bologna, via Selmi 2, 40126 Bologna, Italy.

Optically pure secondary homoallylic amines, obtained by highly diastereoselective addition of allylmetal reagents to imines derived from chiral amines, were N-dealkylated, and the primary amines were converted to N-acryloyl amides. Then, ring closing metathesis gave delta-substituted delta-lactams in good overall yields.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo0703000DOI Listing
August 2007

Asymmetric synthesis of 2-(2-pyridyl)aziridines from 2-pyridineimines bearing stereogenic N-alkyl substituents and regioselective opening of the aziridine ring.

J Org Chem 2006 Dec;71(25):9373-81

Dipartimento di Chimica G. Ciamician, Università di Bologna, via Selmi 2, 40126 Bologna, Italy.

The addition of chloromethyllithium to the imine derived from 2-pyridinecarboxaldehyde and (S)-valinol, protected as its O-trimethylsilyl ether, gave the 1,2-disubstituted aziridine with good yield and diastereoselectivity. The analogous reaction performed on the imine derived from (S)-valine methyl ester gave the product containing the aziridine ring and the alpha-chloro ketone group coming from the attack of chloromethyllithium to the ester function. Other stereogenic alkyl substituents at nitrogen gave less satisfactory results. Moreover, the aziridination protocol did not work on other aromatic imines which were not capable of bidentate chelation, e.g., 3- and 4-pyridineimine and benzaldimine. Preliminary studies showed the possibility to carry out regio- and stereospecific opening reactions of 2-(2-pyridyl)aziridines by attack of internally generated or external nucleophiles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo0614137DOI Listing
December 2006