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1.
J Biol Chem ; 285(22): 17054-64, 2010 May 28.
Article in English | MEDLINE | ID: mdl-20356837

ABSTRACT

Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40-80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.


Subject(s)
Androgens/metabolism , Azasteroids/pharmacology , Hormone Antagonists/pharmacology , Receptors, Androgen/chemistry , Transcription, Genetic , Animals , Azasteroids/chemistry , COS Cells , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Chlorocebus aethiops , Drug Design , Female , Humans , Ligands , Male , Models, Biological , Protein Structure, Tertiary , Rats , Receptors, Cytoplasmic and Nuclear/metabolism , Steroids/metabolism , Transcriptional Activation
2.
J Med Chem ; 52(15): 4578-81, 2009 Aug 13.
Article in English | MEDLINE | ID: mdl-19606870

ABSTRACT

A novel series of 16-substituted-4-azasteroids has been identified as potential tissue-selective androgen receptor modulators. These ligands display potent hAR binding and agonist activity, low virilizing potential, and good pharmacokinetic profiles in dogs. On the basis of its in vitro profile, 21 was evaluated in the OVX and ORX rat models and exhibited an osteoanabolic, tissue-selective profile.


Subject(s)
Azasteroids/chemical synthesis , Receptors, Androgen/drug effects , Androgens , Animals , Azasteroids/pharmacology , Dogs , Drug Design , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Female , Humans , Male , Organ Specificity , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
3.
Mol Cell Biol ; 27(21): 7486-96, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17709391

ABSTRACT

The orphan nuclear receptor Nurr1 is essential for the development and maintenance of midbrain dopaminergic neurons, the cells that degenerate during Parkinson's disease, by promoting the transcription of genes involved in dopaminergic neurotransmission. Since Nurr1 lacks a classical ligand-binding pocket, it is not clear which factors regulate its activity and how these factors are affected during disease pathogenesis. Since Wnt signaling via beta-catenin promotes the differentiation of Nurr1(+) dopaminergic precursors in vitro, we tested for functional interactions between these systems. We found that beta-catenin and Nurr1 functionally interact at multiple levels. In the absence of beta-catenin, Nurr1 is associated with Lef-1 in corepressor complexes. Beta-catenin binds Nurr1 and disrupts these corepressor complexes, leading to coactivator recruitment and induction of Wnt- and Nurr1-responsive genes. We then identified KCNIP4/calsenilin-like protein as being responsive to concurrent activation by Nurr1 and beta-catenin. Since KCNIP4 interacts with presenilins, the Alzheimer's disease-associated proteins that promote beta-catenin degradation, we tested the possibility that KCNIP4 induction regulates beta-catenin signaling. KCNIP4 induction limited beta-catenin activity in a presenilin-dependent manner, thereby serving as a negative feedback loop; furthermore, Nurr1 inhibition of beta-catenin activity was absent in PS1(-/-) cells or in the presence of small interfering RNAs specific to KCNIP4. These data describe regulatory convergence between Nurr1 and beta-catenin, providing a mechanism by which Nurr1 could be regulated by Wnt signaling.


Subject(s)
DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Gene Expression Regulation , Gene Regulatory Networks , Signal Transduction , Transcription Factors/genetics , Transcription Factors/metabolism , Transcription, Genetic , Wnt Proteins/metabolism , Animals , Base Sequence , Cell Line , Cell Nucleus/metabolism , Kv Channel-Interacting Proteins/metabolism , Lymphoid Enhancer-Binding Factor 1/metabolism , Mice , Models, Biological , Molecular Sequence Data , Nuclear Receptor Subfamily 4, Group A, Member 2 , Presenilin-1/metabolism , Protein Binding , Protein Processing, Post-Translational , Rats , Repressor Proteins/metabolism , beta Catenin/metabolism
4.
Bone ; 38(5): 628-36, 2006 May.
Article in English | MEDLINE | ID: mdl-16185944

ABSTRACT

Potent bisphosphonates (BPs) preferentially bind bone at sites of active osteoclastic bone resorption, where they are taken up by the osteoclast and inhibit resorption. We tested the hypothesis that BP affinity to human bone affects antiresorptive potency. [(1)(4)C]-Alendronate binding to human bone was saturable and reversible with an apparent Kd of 72 microM by Scatchard analysis. In competition binding assays, unlabeled alendronate (Ki: 61 microM) was slightly more potent than pyrophosphate (Ki = 156 microM) in blocking [(1)(4)C]-alendronate binding. Likewise, most tested BPs, including etidronate (Ki: 91 microM), ibandronate (116 microM), pamidronate (83 microM), risedronate (85 microM) and zoledronate (81 microM), showed comparable affinities. Interestingly, tiludronate (173 microM; P < 0.05 vs. all other BPs) and especially clodronate (806 microM; P > 0.0001 vs. all other BPs) displayed significantly weaker affinity for bone. The weak affinity of clodronate translated into a requirement for 10-fold higher dosing in in vitro bone resorption assays when bone was pretreated with BP and subsequently washed prior to adding osteoclasts. In stark contrast, neither alendronate nor risedronate lost any efficacy after washing the bone surface. These findings suggest that most clinically tested BPs may have similar affinities for human bone. For those with reduced affinity, this may translate into lower potency that necessitates higher dosing.


Subject(s)
Alendronate/metabolism , Bone Density Conservation Agents/metabolism , Bone Resorption/drug therapy , Bone and Bones/metabolism , Diphosphonates/metabolism , Alendronate/therapeutic use , Animals , Binding, Competitive , Bone Density Conservation Agents/therapeutic use , Diphosphates/metabolism , Diphosphonates/therapeutic use , Humans , Mice , Rats
6.
J Med Chem ; 47(20): 4829-37, 2004 Sep 23.
Article in English | MEDLINE | ID: mdl-15369386

ABSTRACT

3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the alpha(v)beta(3) receptor. These compounds have excellent in vitro profiles (IC(50) = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.


Subject(s)
Integrins/antagonists & inhibitors , Naphthyridines/pharmacology , Osteoporosis/drug therapy , Receptors, Vitronectin/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Bone Density/drug effects , Bone Resorption/drug therapy , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Female , Humans , Inhibitory Concentration 50 , Integrins/metabolism , Macaca mulatta , Models, Molecular , Naphthyridines/chemistry , Naphthyridines/pharmacokinetics , Osteoporosis/prevention & control , Ovariectomy , Rats , Rats, Sprague-Dawley , Receptors, Vitronectin/metabolism , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 14(17): 4411-5, 2004 Sep 06.
Article in English | MEDLINE | ID: mdl-15357963

ABSTRACT

A series of alphaVbeta3 receptor antagonists lacking the amide bond of previously-reported 'chain-shortened' compounds is described. Replacement of the lone amide bond with two methylene groups in this series yields more lipophilic compounds that have longer half-lives, lower clearance, and greater oral bioavailability when administered to dogs.


Subject(s)
Benzenesulfonates/chemistry , Benzenesulfonates/pharmacokinetics , Integrin alphaVbeta3/antagonists & inhibitors , Iodobenzenes/chemistry , Iodobenzenes/pharmacokinetics , Animals , Dogs , Humans , Integrin alphaVbeta3/metabolism
8.
Bioorg Med Chem Lett ; 14(17): 4515-8, 2004 Sep 06.
Article in English | MEDLINE | ID: mdl-15357983

ABSTRACT

Subtle modifications were incorporated into the structure of clinical candidate 1. These changes were designed to maintain potency and selectivity while inducing changes in physical properties leading to improved pharmacokinetics in three species. This approach led to the identification of 4 as a potent, selective alphaVbeta3 receptor antagonist that was selected for clinical development based on an improved PK profile and efficacy demonstrated in an in vivo model of bone turnover.


Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Naphthyridines/chemistry , Animals , Dogs , Drug Evaluation, Preclinical/methods , Humans , Integrin alphaVbeta3/metabolism , Macaca mulatta , Male , Naphthyridines/metabolism , Naphthyridines/pharmacology , Protein Binding/drug effects , Protein Binding/physiology , Rats
9.
Bioorg Med Chem Lett ; 14(4): 1049-52, 2004 Feb 23.
Article in English | MEDLINE | ID: mdl-15013021

ABSTRACT

A series of 3-substituted tetrahydro-[1,8]naphthyridine containing alpha(v)beta(3) antagonists was prepared. A comparison of their in vitro IC(50) values to the electron properties of the 3-substituents revealed a good linear Hammett correlation (rho=-1.96, R(2)=0.959). Electron-withdrawing groups at the 3-position of the tetrahydro-[1,8]naphthyridine decreased potency while electron-donating groups enhanced potency.


Subject(s)
Adrenergic alpha-Antagonists/pharmacology , Adrenergic beta-Antagonists/pharmacology , Integrin alphaVbeta3/antagonists & inhibitors , Naphthyridines/pharmacology , Adrenergic alpha-Antagonists/chemical synthesis , Adrenergic beta-Antagonists/chemical synthesis , Humans , Molecular Structure , Naphthyridines/chemical synthesis , Structure-Activity Relationship
10.
Bioorg Med Chem Lett ; 13(24): 4285-8, 2003 Dec 15.
Article in English | MEDLINE | ID: mdl-14643310

ABSTRACT

Antagonists of the integrin receptor alpha(v)beta(3) are expected to have utility in the treatment of osteoporosis through inhibition of bone resorption. A series of potent, chain-shortened, pyrrolidinone-containing alpha(v)beta(3) receptor antagonists is described. Two sets of diasteromeric pairs of high-affinity antagonists demonstrated marked differences in log P values, which translated into differing dog pharmacokinetic properties. One member of this set was demonstrated to be effective in reducing bone resorption in rats.


Subject(s)
Adrenergic alpha-Antagonists/chemical synthesis , Adrenergic alpha-Antagonists/pharmacology , Adrenergic beta-Antagonists/chemical synthesis , Adrenergic beta-Antagonists/pharmacology , Pyrrolidinones/chemistry , Models, Molecular , Molecular Conformation , Structure-Activity Relationship
11.
J Med Chem ; 46(22): 4790-8, 2003 Oct 23.
Article in English | MEDLINE | ID: mdl-14561098

ABSTRACT

3(S)-(6-methoxypyridin-3-yl)-3-[2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)propyl]imidazolidin-1-yl]propionic acid 6 was identified as a potent and selective antagonist of the alpha(v)beta(3) receptor. This compound has an excellent in vitro profile (IC(50) = 0.08 nM), a significant unbound fraction in human plasma (12%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in three in vivo models of bone turnover, the compound was selected for clinical development. To support the ongoing metabolism and safety studies, a novel strategy was employed in which a series of oxidized derivatives of 6 were prepared by exposure of 6 (or the methyl ester) to chemical oxidizing agents. These products proved useful in the identification of active metabolites generated by either in vitro or in vivo metabolism.


Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Naphthyridines/chemical synthesis , Osteoporosis , Propionates/chemical synthesis , Animals , Bone Density/drug effects , Bone Resorption/drug therapy , Bone Resorption/etiology , Bone Resorption/metabolism , Dogs , Female , Humans , Macaca mulatta , Male , Naphthyridines/chemistry , Naphthyridines/pharmacology , Osteoporosis/drug therapy , Osteoporosis/prevention & control , Ovariectomy , Oxidation-Reduction , Propionates/chemistry , Propionates/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship
12.
Bioorg Med Chem Lett ; 13(10): 1809-12, 2003 May 19.
Article in English | MEDLINE | ID: mdl-12729670

ABSTRACT

Two novel series of small-molecule RGD mimetics containing either a substituted pyridone or pyrazinone central constraint were prepared. Modification of the beta-alanine 3-substituent produced compounds that are potent and selective alpha(v)beta(3) antagonists and exhibit a range of physicochemical properties.


Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Pyrazines/chemistry , Pyridones/chemistry , Alanine/chemistry , Drug Design , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Molecular Mimicry , Oligopeptides , Protein Binding , Pyrazines/pharmacokinetics , Pyridones/pharmacokinetics , Radioimmunoassay , Structure-Activity Relationship
13.
J Med Chem ; 45(26): 5640-8, 2002 Dec 19.
Article in English | MEDLINE | ID: mdl-12477347

ABSTRACT

A binding model for nonpeptide antagonists of integrin alpha(v)beta(3) has been developed through docking analyses utilizing the MMFFs force field and the recently published crystal structure, 1JV2. Results of this docking study have led to the identification of a novel binding model for selective antagonists of alpha(v)beta(3) over alpha(IIb)beta(3) integrins. Four different chemical classes are shown to bind in a similar fashion providing a measure of confidence in the proposed model. All alpha(v)beta(3) and alpha(IIb)beta(3) antagonists have a basic nitrogen separated some distance from a carboxylic acid to mimic RGD. For the alpha(v)beta(3) antagonists under present consideration, these charged ends are separated by twelve bonds. The basic nitrogen of the active alpha(v)beta(3) ligands are shown to interact with D150 of alpha(v) and the ligands' carboxylic acid interact with R214 of beta(3) while adopting an extended conformation with minimal protein induced internal strain. In addition, an energetically favorable interaction is found with all of the active alpha(v)beta(3) molecules with Y178 of alpha(v) when docked to the crystallographically determined structure. This novel interaction may be characterized as pi-pi stacking for the most active of the alpha(v)beta(3) selective antagonists. The proposed model is consistent with observed activity as well as mutagenicity and photoaffinity cross-linking studies of the alpha(v)beta(3) integrin.


Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Benzazepines/chemistry , Binding Sites , Glycine/analogs & derivatives , Glycine/chemistry , Heterocyclic Compounds/chemistry , Integrin alphaVbeta3/chemistry , Ligands , Models, Molecular , Sulfonamides/chemistry
14.
Bioorg Med Chem Lett ; 12(17): 2463-5, 2002 Sep 02.
Article in English | MEDLINE | ID: mdl-12161158

ABSTRACT

Potent non-peptidic alpha(v)beta(3) antagonists have been prepared where deletion of an amide bond from an earlier series of linear RGD-mimetics provides a novel series of chain-shortened alpha(v)beta(3) antagonists with significantly improved oral pharmacokinetics. These chain-shortened alpha(v)beta(3) antagonists represent structurally novel integrin inhibitors.


Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Oligopeptides/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Dogs , Half-Life , Inhibitory Concentration 50 , Metabolic Clearance Rate , Molecular Mimicry , Oligopeptides/administration & dosage , Oligopeptides/pharmacology , Structure-Activity Relationship
15.
Bioorg Med Chem Lett ; 12(1): 25-9, 2002 Jan 07.
Article in English | MEDLINE | ID: mdl-11738566

ABSTRACT

Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor, alpha(v)beta(3). The use of the 5,6,7,8-tetrahydro[1,8]naphthyridine group as a potency-enhancing N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in alpha(IIb)beta(3) antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor. Further affinity increases were then achieved through the use of cyclic glycyl amide bond constraints.


Subject(s)
Oligopeptides/pharmacology , Receptors, Vitronectin/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Binding, Competitive , Drug Design , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Molecular Conformation , Molecular Mimicry , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Osteoporosis/prevention & control , Platelet Aggregation/drug effects , Receptors, Vitronectin/metabolism , Structure-Activity Relationship
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