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1.
ACS Med Chem Lett ; 9(12): 1170-1174, 2018 Dec 13.
Article in English | MEDLINE | ID: mdl-30613321

ABSTRACT

BMS-823778 (2), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) enzyme (IC50 = 2.3 nM) with >10,000-fold selectivity over 11ß-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50 = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED50 = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50 = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.

2.
J Mol Biol ; 428(14): 2860-79, 2016 07 17.
Article in English | MEDLINE | ID: mdl-27216500

ABSTRACT

Current clinical anti-CD40 biologic agents include both antagonist molecules for the treatment of autoimmune diseases and agonist molecules for immuno-oncology, yet the relationship between CD40 epitope and these opposing biological outcomes is not well defined. This report describes the identification of potent antagonist domain antibodies (dAbs) that bind to a novel human CD40-specific epitope that is divergent in the CD40 of nonhuman primates. A similarly selected anti-cynomolgus CD40 dAb recognizing the homologous epitope is also a potent antagonist. Mutagenesis, biochemical, and X-ray crystallography studies demonstrate that the epitope is distinct from that of CD40 agonists. Both the human-specific and cynomolgus-specific molecules remain pure antagonists even when formatted as bivalent Fc-fusion proteins, making this an attractive therapeutic format for targeting hCD40 in autoimmune indications.


Subject(s)
CD40 Antigens/immunology , Epitopes/immunology , Animals , Autoimmune Diseases/immunology , Crystallography, X-Ray/methods , Humans , Macaca fascicularis
3.
Bioorg Med Chem ; 24(10): 2257-72, 2016 05 15.
Article in English | MEDLINE | ID: mdl-27073051

ABSTRACT

Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-23. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system.


Subject(s)
Anticoagulants/chemistry , Anticoagulants/pharmacology , Factor XIa/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Administration, Oral , Animals , Anticoagulants/administration & dosage , Anticoagulants/pharmacokinetics , Blood Coagulation/drug effects , Crystallography, X-Ray , Dogs , Factor XIa/metabolism , Humans , Models, Molecular , Phenylcarbamates/administration & dosage , Phenylcarbamates/chemistry , Phenylcarbamates/pharmacokinetics , Phenylcarbamates/pharmacology , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics
4.
Bioorg Med Chem Lett ; 26(2): 472-478, 2016 Jan 15.
Article in English | MEDLINE | ID: mdl-26704266

ABSTRACT

The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50=2.8µM) in the rabbit electrically induced carotid arterial thrombosis model (ECAT).


Subject(s)
Anilides/pharmacology , Factor XIa/antagonists & inhibitors , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacology , Anilides/chemical synthesis , Animals , Crystallography, X-Ray , Dogs , Phenylalanine/chemical synthesis , Rabbits , Structure-Activity Relationship
5.
Acta Crystallogr F Struct Biol Commun ; 71(Pt 10): 1273-81, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26457518

ABSTRACT

The structure of death receptor 4 (DR4) in complex with TNF-related apoptosis-inducing ligand (TRAIL) has been determined at 3 Šresolution and compared with those of previously determined DR5-TRAIL complexes. Consistent with the high sequence similarity between DR4 and DR5, the overall arrangement of the DR4-TRAIL complex does not differ substantially from that of the DR5-TRAIL complex. However, subtle differences are apparent. In addition, solution interaction studies were carried out that show differences in the thermodynamics of binding DR4 or DR5 with TRAIL.


Subject(s)
Receptors, TNF-Related Apoptosis-Inducing Ligand/chemistry , TNF-Related Apoptosis-Inducing Ligand/chemistry , Amino Acid Sequence , Calorimetry , Crystallization , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Sequence Data , Protein Binding , Receptors, TNF-Related Apoptosis-Inducing Ligand/isolation & purification , TNF-Related Apoptosis-Inducing Ligand/isolation & purification , Thermodynamics
6.
ACS Med Chem Lett ; 6(5): 590-5, 2015 May 14.
Article in English | MEDLINE | ID: mdl-26005539

ABSTRACT

Structure-activity relationship optimization of phenylalanine P1' and P2' regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2' group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC2x of 1.0 µM. Dose-dependent efficacy (EC50 of 0.53 µM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation.

7.
Bioorg Med Chem Lett ; 25(7): 1635-42, 2015 Apr 01.
Article in English | MEDLINE | ID: mdl-25728130

ABSTRACT

Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.7 nM and modest oral exposure in dogs.


Subject(s)
Drug Design , Enzyme Inhibitors/pharmacology , Factor XIa/antagonists & inhibitors , Indazoles/pharmacology , Administration, Oral , Animals , Biological Availability , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Factor XIa/drug effects , Humans , Indazoles/administration & dosage , Indazoles/chemistry , Models, Molecular , Molecular Structure , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 25(4): 925-30, 2015 Feb 15.
Article in English | MEDLINE | ID: mdl-25592713

ABSTRACT

The structure-activity relationships (SAR) of six-membered ring replacements for the imidazole ring scaffold is described. This work led to the discovery of the potent and selective pyridine (S)-23 and pyridinone (±)-24 factor XIa inhibitors. SAR and X-ray crystal structure data highlight the key differences between imidazole and six-membered ring analogs.


Subject(s)
Factor XIa/antagonists & inhibitors , Pyridines/pharmacology , Pyridones/pharmacology , Crystallography, X-Ray , Models, Molecular , Structure-Activity Relationship
9.
J Med Chem ; 57(23): 9915-32, 2014 Dec 11.
Article in English | MEDLINE | ID: mdl-25405503

ABSTRACT

Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.


Subject(s)
Fibrinolytic Agents/chemical synthesis , Imidazoles/chemical synthesis , Indazoles/chemical synthesis , Animals , Crystallography, X-Ray , Fibrinolytic Agents/pharmacokinetics , Fibrinolytic Agents/pharmacology , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Indazoles/pharmacokinetics , Indazoles/pharmacology , Models, Molecular , Partial Thromboplastin Time , Rabbits , Thrombosis/prevention & control
10.
J Med Chem ; 57(3): 955-69, 2014 Feb 13.
Article in English | MEDLINE | ID: mdl-24405333

ABSTRACT

Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound 1 was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in animal models with a reversible, small molecule inhibitor.


Subject(s)
Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Quinolines/chemical synthesis , Animals , Bleeding Time , Crystallography, X-Ray , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Humans , Molecular Conformation , Molecular Docking Simulation , Quinolines/chemistry , Quinolines/pharmacology , Rabbits , Stereoisomerism , Structure-Activity Relationship
11.
Structure ; 20(2): 259-69, 2012 Feb 08.
Article in English | MEDLINE | ID: mdl-22325775

ABSTRACT

Adnectins are targeted biologics derived from the tenth type III domain of human fibronectin (¹°Fn3), a member of the immunoglobulin superfamily. Target-specific binders are selected from libraries generated by diversifying the three ¹°Fn3 loops that are analogous to the complementarity determining regions of antibodies. The crystal structures of two Adnectins were determined, each in complex with its therapeutic target, EGFR or IL-23. Both Adnectins bind different epitopes than those bound by known monoclonal antibodies. Molecular modeling suggests that some of these epitopes might not be accessible to antibodies because of the size and concave shape of the antibody combining site. In addition to interactions from the Adnectin diversified loops, residues from the N terminus and/or the ß strands interact with the target proteins in both complexes. Alanine-scanning mutagenesis confirmed the calculated binding energies of these ß strand interactions, indicating that these nonloop residues can expand the available binding footprint.


Subject(s)
ErbB Receptors/chemistry , Fibronectins/chemistry , Interleukin-23/chemistry , Peptide Fragments/chemistry , Amino Acid Sequence , Amino Acid Substitution , Crystallography, X-Ray , Fibronectins/genetics , Humans , Hydrogen Bonding , Models, Molecular , Molecular Sequence Data , Multiprotein Complexes/chemistry , Mutagenesis, Site-Directed , Peptide Fragments/genetics , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Quaternary , Protein Structure, Secondary , Structural Homology, Protein , Surface Plasmon Resonance , Surface Properties
12.
Bioorg Med Chem Lett ; 21(1): 537-41, 2011 Jan 01.
Article in English | MEDLINE | ID: mdl-21078556

ABSTRACT

Heterocyclic replacement of the isophthalamide phenyl ring in hydroxyethylamine (HEA) BACE-1 inhibitors was explored. A variety of indole-1,3-dicarboxamide HEAs exhibited potent BACE-1 enzyme inhibition, but displayed poor cellular activity. Improvements in cellular activity and aspartic protease selectivity were observed for 7-azaindole-1,3-dicarboxamide HEAs. A methylprolinol-bearing derivative (10n) demonstrated robust reductions in rat plasma Aß levels, but did not lower rat brain Aß due to poor central exposure. The same analog exhibited a high efflux ratio in a bidirectional Caco-2 assay and was likely a substrate of the efflux transporter P-glycoprotein. X-ray crystal structures are reported for two indole HEAs in complex with BACE-1.


Subject(s)
Amines/chemistry , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Indoles/chemical synthesis , Protease Inhibitors/chemistry , Pyridines/chemical synthesis , Amines/chemical synthesis , Amines/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/blood , Animals , Aspartic Acid Endopeptidases/metabolism , Binding Sites , Crystallography, X-Ray , Indoles/chemistry , Indoles/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Protein Structure, Tertiary , Pyridines/chemistry , Pyridines/pharmacology , Rats , Structure-Activity Relationship
13.
Arch Biochem Biophys ; 410(2): 307-16, 2003 Feb 15.
Article in English | MEDLINE | ID: mdl-12573291

ABSTRACT

Amyloid precursor protein (APP) cleaving enzyme (BACE) is the enzyme responsible for beta-site cleavage of APP, leading to the formation of the amyloid-beta peptide that is thought to be pathogenic in Alzheimer's disease (AD). Hence, BACE is an attractive pharmacological target, and numerous research groups have begun searching for potent and selective inhibitors of this enzyme as a potential mechanism for therapeutic intervention in AD. The mature enzyme is composed of a globular catalytic domain that is N-linked glycosylated in mammalian cells, a single transmembrane helix that anchors the enzyme to an intracellular membrane, and a short C-terminal domain that extends outside the phospholipid bilayer of the membrane. Here we have compared the substrate and active site-directed inhibitor binding properties of several recombinant constructs of human BACE. The constructs studied here address the importance of catalytic domain glycosylation state, inclusion of domains other than the catalytic domain, and incorporation into a membrane bilayer on the interactions of the enzyme active site with peptidic ligands. We find no significant differences in ligand binding properties among these various constructs. These data demonstrate that the nonglycosylated, soluble catalytic domain of BACE faithfully reflects the ligand binding properties of the full-length mature enzyme in its natural membrane environment. Thus, the use of the nonglycosylated, soluble catalytic domain of BACE is appropriate for studies aimed at understanding the determinants of ligand recognition by the enzyme active site.


Subject(s)
Aspartic Acid Endopeptidases/chemistry , Recombinant Proteins/chemistry , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases , Animals , Aspartic Acid Endopeptidases/metabolism , Binding Sites , CHO Cells , Catalysis , Catalytic Domain , Cell Line , Cell Membrane/metabolism , Chromatography, High Pressure Liquid , Cricetinae , Dose-Response Relationship, Drug , Drosophila , Endopeptidases , Escherichia coli/metabolism , Glycosylation , Humans , Inhibitory Concentration 50 , Kinetics , Ligands , Light , Lipid Bilayers/metabolism , Peptides/chemistry , Protein Binding , Protein Structure, Tertiary , Recombinant Proteins/metabolism , Scattering, Radiation , Time Factors
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