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1.
J Med Chem ; 67(13): 11103-11124, 2024 Jul 11.
Article in English | MEDLINE | ID: mdl-38907711

ABSTRACT

A hit-to-lead campaign pursuing the identification of novel inhalant small-molecule phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of inflammatory respiratory diseases is disclosed. A synthetically versatile pyridazin-3(2H)-one scaffold was designed, and three exit vectors on the core moiety were used to explore chemical diversity and optimize pharmacological and absorption, distribution, metabolism, and excretion (ADME) properties. Desired modulation of PI3Kδ selectivity and cellular potency as well as ADME properties in view of administration by inhalation was achieved. Intratracheal administration of lead compound 26 resulted in a promising pharmacokinetic profile, thus demonstrating that the optimization strategy of in vitro profiles successfully translated to an in vivo setting.


Subject(s)
Class I Phosphatidylinositol 3-Kinases , Phosphoinositide-3 Kinase Inhibitors , Pyridazines , Animals , Humans , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors/chemistry , Phosphoinositide-3 Kinase Inhibitors/pharmacokinetics , Phosphoinositide-3 Kinase Inhibitors/chemical synthesis , Administration, Inhalation , Pyridazines/chemistry , Pyridazines/pharmacology , Pyridazines/pharmacokinetics , Pyridazines/chemical synthesis , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class I Phosphatidylinositol 3-Kinases/metabolism , Structure-Activity Relationship , Drug Discovery , Rats , Mice , Male , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/administration & dosage
2.
Eur J Med Chem ; 254: 115331, 2023 Jun 05.
Article in English | MEDLINE | ID: mdl-37094451

ABSTRACT

PI3Kδ is a lipid kinase which plays a key role in airway inflammatory conditions. Accordingly, the inhibition of PI3Kδ can be considered a valuable strategy for the treatment of chronic respiratory diseases such as Asthma and Chronic obstructive pulmonary disease (COPD). In this work, we describe our efforts to identify new PI3Kδ inhibitors following an "inhalation by design" strategy. Starting from the identification of a purine scaffold, we carried out a preliminary SAR expansion which led to the identification of a new hit characterized by a high enzymatic potency and moderate PI3Kδ selectivity. A subsequent optimization led to novel purine based derivatives with favorable in vitro ADME profiles, which might represent promising starting points for future development of new inhaled drug candidates.


Subject(s)
Asthma , Pulmonary Disease, Chronic Obstructive , Humans , Asthma/drug therapy , Pulmonary Disease, Chronic Obstructive/drug therapy , Administration, Inhalation , Purines/pharmacology , Purines/therapeutic use , Class I Phosphatidylinositol 3-Kinases
4.
Anal Chem ; 88(19): 9510-9517, 2016 10 04.
Article in English | MEDLINE | ID: mdl-27583774

ABSTRACT

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 R2 value was higher than 0.86, while the best Q2 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 (R2), prediction (Q2), 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.


Subject(s)
Chromatography, Liquid , Models, Chemical , Algorithms , Least-Squares Analysis , Principal Component Analysis
5.
J Med Chem ; 59(7): 3392-408, 2016 Apr 14.
Article in English | MEDLINE | ID: mdl-27003761

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Drug Discovery , Indazoles/pharmacology , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Administration, Oral , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Benzamides/administration & dosage , Benzamides/chemistry , Blood-Brain Barrier/drug effects , Blotting, Western , Cell Membrane Permeability/drug effects , Cell Proliferation/drug effects , Crystallization , Crystallography, X-Ray , Dogs , Humans , Indazoles/administration & dosage , Indazoles/chemistry , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mice, Nude , Mice, SCID , Microsomes, Liver/drug effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins/antagonists & inhibitors , Rats , Rats, Wistar , Receptor, trkA/antagonists & inhibitors , Receptor, trkB/antagonists & inhibitors , Receptor, trkC/antagonists & inhibitors , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
6.
Bioorg Med Chem ; 21(22): 7047-63, 2013 Nov 15.
Article in English | MEDLINE | ID: mdl-24100158

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Isoxazoles/chemistry , Isoxazoles/pharmacology , Animals , Antineoplastic Agents/therapeutic use , Binding Sites , Biomarkers, Tumor/metabolism , Catalytic Domain , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , Female , HSP90 Heat-Shock Proteins/metabolism , Humans , Isoxazoles/therapeutic use , Mice , Mice, Inbred BALB C , Mice, Nude , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Protein Binding/drug effects , Structure-Activity Relationship , Transplantation, Heterologous
7.
J Med Chem ; 56(17): 6917-34, 2013 Sep 12.
Article in English | MEDLINE | ID: mdl-23991897

ABSTRACT

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 ß-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 ß-lactone analogues of compound 4. The main results of this work were an enhancement of the inhibitory potency of ß-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).


Subject(s)
Amidohydrolases/antagonists & inhibitors , Carbamates/chemistry , Carbamates/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Base Sequence , Carbamates/chemical synthesis , DNA Primers , Magnetic Resonance Spectroscopy , Models, Molecular , Spectroscopy, Fourier Transform Infrared , Structure-Activity Relationship , Tandem Mass Spectrometry
8.
J Med Chem ; 56(14): 5917-30, 2013 Jul 25.
Article in English | MEDLINE | ID: mdl-23822179

ABSTRACT

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.


Subject(s)
Amidohydrolases/antagonists & inhibitors , Carbamates/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Animals , Carbamates/pharmacology , Enzyme Inhibitors/pharmacology , Male , Mice , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 20(14): 4095-9, 2010 Jul 15.
Article in English | MEDLINE | ID: mdl-20621725

ABSTRACT

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.


Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , 3-Phosphoinositide-Dependent Protein Kinases , Cell Line, Tumor , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/pharmacology
10.
J Org Chem ; 72(16): 6022-8, 2007 Aug 03.
Article in English | MEDLINE | ID: mdl-17625880

ABSTRACT

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.

11.
J Org Chem ; 71(25): 9373-81, 2006 Dec 08.
Article in English | MEDLINE | ID: mdl-17137364

ABSTRACT

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.


Subject(s)
Aziridines/chemical synthesis , Imines/chemistry , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization , Stereoisomerism
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