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1.
Mol Cancer Ther ; 16(12): 2677-2688, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29054982

ABSTRACT

NAMPT, an enzyme essential for NAD+ biosynthesis, has been extensively studied as an anticancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective and has a potent and broad spectrum of anticancer activity. Its inhibitory activity can be rescued with nicotinic acid (NA) against the cell lines proficient, but not those deficient in NAPRT1, essential for converting NA to NAD+ LSN3154567 also exhibits robust efficacy in multiple tumor models deficient in NAPRT1. Importantly, this molecule when coadministered with NA does not cause observable retinal and hematological toxicities in the rodents, yet still retains robust efficacy. Thus, LSN3154567 has the potential to be further developed clinically into a novel cancer therapeutic. Mol Cancer Ther; 16(12); 2677-88. ©2017 AACR.


Subject(s)
Cytokines/antagonists & inhibitors , Niacin/therapeutic use , Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors , Retinal Pigment Epithelium/drug effects , Animals , Humans , Mice , Niacin/pharmacology , Retinal Pigment Epithelium/pathology
2.
Invest New Drugs ; 32(5): 825-37, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24919854

ABSTRACT

The G1 restriction point is critical for regulating the cell cycle and is controlled by the Rb pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). This pathway is important because of its inactivation in a majority of human tumors. Transition through the restriction point requires phosphorylation of retinoblastoma protein (Rb) by CDK4/6, which are highly validated cancer drug targets. We present the identification and characterization of a potent CDK4/6 inhibitor, LY2835219. LY2835219 inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. In vivo target inhibition studies show LY2835219 is a potent inhibitor of Rb phosphorylation, induces a complete cell cycle arrest and suppresses expression of several Rb-E2F-regulated proteins 24 hours after a single dose. Oral administration of LY2835219 inhibits tumor growth in human tumor xenografts representing different histologies in tumor-bearing mice. LY2835219 is effective and well tolerated when administered up to 56 days in immunodeficient mice without significant loss of body weight or tumor outgrowth. In calu-6 xenografts, LY2835219 in combination with gemcitabine enhanced in vivo antitumor activity without a G1 cell cycle arrest, but was associated with a reduction of ribonucleotide reductase expression. These results suggest LY2835219 may be used alone or in combination with standard-of-care cytotoxic therapy. In summary, we have identified a potent, orally active small-molecule inhibitor of CDK4/6 that is active in xenograft tumors. LY2835219 is currently in clinical development.


Subject(s)
Aminopyridines/pharmacology , Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Aminopyridines/therapeutic use , Animals , Antineoplastic Agents/therapeutic use , Benzimidazoles/therapeutic use , Cell Line, Tumor , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Drug Therapy, Combination , Female , G1 Phase Cell Cycle Checkpoints/drug effects , Humans , Mice , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Phosphorylation/drug effects , Protein Kinase Inhibitors/therapeutic use , Retinoblastoma Protein/antagonists & inhibitors , Retinoblastoma Protein/metabolism , Tumor Burden/drug effects , Xenograft Model Antitumor Assays , Gemcitabine
3.
Bioorg Med Chem Lett ; 23(23): 6459-62, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24119554

ABSTRACT

The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.


Subject(s)
Isoquinolines/pharmacology , Pain/drug therapy , Prodrugs/pharmacology , Receptors, Kainic Acid/antagonists & inhibitors , Administration, Oral , Amino Acid Sequence , Animals , Disease Models, Animal , Haplorhini , Isoquinolines/chemistry , Molecular Sequence Data , Prodrugs/chemistry , Receptors, Kainic Acid/chemistry , Structure-Activity Relationship
4.
Bioorg Med Chem Lett ; 23(23): 6463-6, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24140446

ABSTRACT

We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.


Subject(s)
Isoquinolines/pharmacology , Pain/drug therapy , Prodrugs/pharmacology , Receptors, Kainic Acid/antagonists & inhibitors , Tetrazoles/pharmacology , Administration, Oral , Amino Acid Sequence , Animals , Disease Models, Animal , Isoquinolines/chemistry , Male , Molecular Sequence Data , Prodrugs/chemistry , Rats , Rats, Sprague-Dawley , Receptors, Kainic Acid/chemistry , Structure-Activity Relationship , Tetrazoles/chemistry
5.
Bioorg Med Chem Lett ; 18(1): 179-83, 2008 Jan 01.
Article in English | MEDLINE | ID: mdl-18039577

ABSTRACT

Herein we report investigations into the p38alpha MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Imidazoles/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Pyridines/pharmacology , Adenosine Triphosphate/analogs & derivatives , Adenosine Triphosphate/metabolism , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Edema/drug therapy , ErbB Receptors/metabolism , Humans , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Mice , Mice, Inbred BALB C , Peptide Fragments/metabolism , Pyridines/chemistry , Pyridines/pharmacokinetics , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism
6.
J Med Chem ; 48(13): 4200-3, 2005 Jun 30.
Article in English | MEDLINE | ID: mdl-15974569

ABSTRACT

Amino acids 5 and 7, two potent and selective competitive GluR5 KA receptor antagonists, exhibited high GluR5 receptor affinity over other glutamate receptors. Their ester prodrugs 6 and 8 were orally active in three models of pain: reversal of formalin-induced paw licking, carrageenan-induced thermal hyperalgesia, and capsaicin-induced mechanical hyperalgesia.


Subject(s)
Amino Acids/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Pain/drug therapy , Receptors, Kainic Acid/antagonists & inhibitors , Analgesics/pharmacokinetics , Animals , Biological Availability , Cell Line , Disease Models, Animal , Humans , Hyperalgesia/drug therapy , Rats , Receptors, AMPA/metabolism , Recombinant Proteins/metabolism , Spinal Cord/physiopathology , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism
7.
J Med Chem ; 48(7): 2270-3, 2005 Apr 07.
Article in English | MEDLINE | ID: mdl-15801819

ABSTRACT

We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38alphainhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFalpha release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR strategy to address CyP3A4 liability is also described.


Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Benzimidazoles/chemical synthesis , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Arthritis, Experimental/drug therapy , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Binding Sites , Biological Availability , Collagen , Crystallography, X-Ray , Drug Design , Humans , Lipopolysaccharides/pharmacology , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/metabolism , Mice , Mice, Inbred BALB C , Mitogen-Activated Protein Kinase 14/chemistry , Models, Molecular , Rats , Tumor Necrosis Factor-alpha/antagonists & inhibitors
8.
Bioorg Med Chem Lett ; 14(24): 6095-9, 2004 Dec 20.
Article in English | MEDLINE | ID: mdl-15546737

ABSTRACT

We have identified a novel structural class of protein serine/threonine kinase inhibitors comprised of an aminoimidazo[1,2-a]pyridine nucleus. Compounds from this family are shown to potently inhibit cyclin-dependent kinases by competing with ATP for binding to a catalytic subunit of the protein. Structure-based design approach was used to direct this chemical scaffold toward generating potent and selective CDK2 inhibitors. The discovery of this new class of ATP-site directed protein kinase inhibitors, aminoimidazo[1,2-a]pyridines, provides the basis of new medicinal chemistry tool in search for an effective treatment of cancer and other diseases that involve protein kinase signaling pathways.


Subject(s)
Cyclin-Dependent Kinases/antagonists & inhibitors , Imidazoles , Pyridines , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Structure-Activity Relationship
9.
J Org Chem ; 69(13): 4454-63, 2004 Jun 25.
Article in English | MEDLINE | ID: mdl-15202901

ABSTRACT

The reactions of lithium carbanions derived from both enantiomers of methyl (1) and ethyl p-tolyl sulfoxide (2) with (S)-N-arylsulfinylketimines 3 and 4 took place in a highly stereoselective manner and good isolated yields. The configuration of the carbon bonded to nitrogen relies exclusively on the N-sulfinylimine configuration. When ethyl p-tolyl sulfoxide (2) is use as nucleophile, two chiral centers are created simultaneously, where the configuration of the carbon bonded to the sulfur is mainly controlled by 2. The asymmetric induction increases with the temperature, being total at room temperature in the case of the matched pair of reactants. A non-oxidative Pummerer reaction on the obtained aminosulfoxides allows a straightforward synthesis of optically pure 1,2-ethanolamines with one or two chiral centers, including amino alcohols with a bulky quaternary carbon bonded to the amine group.

10.
J Med Chem ; 46(20): 4333-41, 2003 Sep 25.
Article in English | MEDLINE | ID: mdl-13678411

ABSTRACT

A novel structural class of picornavirus inhibitors comprising an imidazo[1,2-b]pyridazine nucleus was discovered. 2-Aminoimidazo[1,2-b]pyridazines (6d, (E/Z)-7b, (E)-7d, (Z)-7d, (E/Z)-8b, (E)-10b, (E)-13a, (Z)-13a, (E)-13b, (Z)-13b, (E)-13c, and (Z)-13c) were designed and synthesized in an effort to identify potent broad spectrum antirhinoviral agents. A practical synthetic route to this chemical scaffold has been developed. The target compounds were evaluated in a plaque reduction assay and in a cytopathic effect assay. Our preliminary SAR studies highlight the minimum structural features required for antirhinovirus activity. Our data suggest that the nature of the linker between the phenyl and the imidazopyridazine moieties has a significant influence on the activity of these compounds. Oximes are slightly better than vinyl carboxamides at this position. The oximes are the most potent analogues against human rhinovirus 14 (HRV-14), and at the concentrations evaluated, no apparent cellular toxicity is noted. Furthermore, the E geometry appears to be a key element for activity; the Z isomer leads to a considerable loss in potency. Of particular interest, analogue 7b exhibits potent broad-spectrum antirhinoviral and antienteroviral activity when evaluated against a panel of seven additional rhino- and enteroviruses. The chemistry and the biological evaluations are discussed.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Picornaviridae/drug effects , Pyridazines/chemistry , Pyridazines/pharmacology , Antiviral Agents/chemical synthesis , Drug Design , Humans , Imidazoles/chemical synthesis , Isomerism , Pyridazines/chemical synthesis , Structure-Activity Relationship
11.
J Med Chem ; 45(20): 4383-6, 2002 Sep 26.
Article in English | MEDLINE | ID: mdl-12238915

ABSTRACT

Amino diacid 3, a highly selective competitive GluR5 kainate receptor antagonist, exhibited high GluR5 receptor affinity and selectivity over other glutamate receptors. Its diethyl ester prodrug 4 was orally active in two models of migraine: the neurogenic dural plasma protein extravasation model and the nucleus caudalis c-fos expression model. These data suggest that a GluR5 kainate receptor antagonist might be an efficacious antimigraine therapy with a novel mechanism of action.


Subject(s)
Carboxylic Acids/chemical synthesis , Esters/chemical synthesis , Excitatory Amino Acid Antagonists/chemical synthesis , Isoquinolines/chemical synthesis , Migraine Disorders/drug therapy , Prodrugs/chemical synthesis , Receptors, Kainic Acid/antagonists & inhibitors , Acute Disease , Administration, Oral , Animals , Biological Availability , Calcium/metabolism , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Cell Line , Disease Models, Animal , Dose-Response Relationship, Drug , Esters/chemistry , Esters/pharmacology , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/pharmacology , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacology , Prodrugs/chemistry , Prodrugs/pharmacology , Radioligand Assay , Rats , Rats, Wistar
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