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1.
J Med Chem ; 67(5): 3571-3589, 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38385264

ABSTRACT

PAR4 is a promising antithrombotic target with potential for separation of efficacy from bleeding risk relative to current antiplatelet therapies. In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based HTS hit 3 with low µM potency was identified. Optimization of the HTS hit through the use of positional SAR scanning and the design of conformationally constrained cores led to the discovery of a quinoxaline-benzothiazole series as potent and selective PAR4 antagonists. The lead compound 48, possessing a 2 nM IC50 against PAR4 activation by γ-thrombin in platelet-rich plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated robust antithrombotic efficacy and minimal bleeding in the cynomolgus monkey models.


Subject(s)
Fibrinolytic Agents , Thrombosis , Animals , Fibrinolytic Agents/pharmacology , Fibrinolytic Agents/therapeutic use , Macaca fascicularis , Quinoxalines/pharmacology , Quinoxalines/therapeutic use , Receptors, Thrombin , Thrombin , Hemorrhage , Thrombosis/drug therapy , Thrombosis/prevention & control , Receptor, PAR-1 , Blood Platelets , Platelet Aggregation
2.
J Med Chem ; 65(13): 8843-8854, 2022 07 14.
Article in English | MEDLINE | ID: mdl-35729784

ABSTRACT

Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (43), and a backup clinical candidate, BMS-986141 (49). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.


Subject(s)
Platelet Aggregation , Thrombosis , Benzofurans , Blood Platelets , Humans , Imidazoles , Morpholines , Receptor, PAR-1 , Receptors, Thrombin , Thiazoles , Thrombin , Thrombosis/drug therapy
3.
J Med Chem ; 64(21): 15549-15581, 2021 11 11.
Article in English | MEDLINE | ID: mdl-34709814

ABSTRACT

The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1 Kb of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).


Subject(s)
Drug Discovery , Pulmonary Fibrosis/drug therapy , Receptors, Lysophosphatidic Acid/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , Male , Mice , Molecular Structure , Pulmonary Fibrosis/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Lysophosphatidic Acid/metabolism , Structure-Activity Relationship
4.
J Med Chem ; 63(23): 15050-15071, 2020 12 10.
Article in English | MEDLINE | ID: mdl-33261314

ABSTRACT

Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.


Subject(s)
Naphthyridines/pharmacology , Quinolines/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Drug Design , Female , Humans , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Molecular Structure , Naphthyridines/chemical synthesis , Naphthyridines/pharmacokinetics , Naphthyridines/therapeutic use , Proof of Concept Study , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Quinolines/therapeutic use , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolism
5.
Bioorg Med Chem Lett ; 30(21): 127495, 2020 11 01.
Article in English | MEDLINE | ID: mdl-32798651

ABSTRACT

Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed.


Subject(s)
Amides/pharmacology , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , rho-Associated Kinases/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Animals , Blood Pressure/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Mice , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity Relationship , rho-Associated Kinases/metabolism
6.
Bioorg Med Chem Lett ; 30(3): 126856, 2020 02 01.
Article in English | MEDLINE | ID: mdl-31870650

ABSTRACT

The objective of this Letter is to report the first (to our knowledge) in vivo proof of concept for a sulfenamide prodrug to orally deliver a poorly soluble drug containing a weakly-acidic NH-acid from a conventional solid dosage formulation. This proof of concept was established using BMS-708163 (1), a gamma secretase inhibitor containing a weakly acidic primary amide NH-acid as the chemical handle for attaching a series of thiol-based promoieties via a sulfenamide linkage. Aqueous stabilities and solubilities are reported for a series of six sulfenamide prodrugs (2-7) of 1. The sulfenamide prodrug containing the cysteine methyl ester promoiety (5) was chosen for a orally-dosed PK study in male beagle dog comparing a solubilized formulation of 1 against a solid dosage form of 5 in a cross-over fashion at an equivalent molar dose of 3 mg/kg. Prodrug 5 delivered essentially a superimposable PK profile of 1 compared to the solubilized formulation of 1, without any detectable exposure of 5 in systemic circulation.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Oxadiazoles/chemistry , Prodrugs/chemistry , Sulfamerazine/chemistry , Sulfonamides/chemistry , Administration, Oral , Amyloid Precursor Protein Secretases/metabolism , Animals , Capsules/chemistry , Dogs , Drug Stability , Half-Life , Male , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Solubility , Sulfamerazine/chemical synthesis , Sulfamerazine/pharmacokinetics
7.
J Med Chem ; 62(16): 7400-7416, 2019 08 22.
Article in English | MEDLINE | ID: mdl-31246024

ABSTRACT

In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.


Subject(s)
Benzofurans/pharmacology , Fibrinolytic Agents/pharmacology , Hemorrhage/prevention & control , Receptors, Thrombin/antagonists & inhibitors , Thrombosis/prevention & control , Animals , Benzofurans/chemistry , Benzofurans/pharmacokinetics , Biological Availability , Disease Models, Animal , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacokinetics , HEK293 Cells , Hemorrhage/metabolism , Humans , Macaca fascicularis , Models, Chemical , Molecular Structure , Platelet Aggregation/drug effects , Receptors, Thrombin/genetics , Receptors, Thrombin/metabolism , Structure-Activity Relationship , Thrombosis/metabolism
8.
ACS Med Chem Lett ; 6(5): 523-7, 2015 May 14.
Article in English | MEDLINE | ID: mdl-26005526

ABSTRACT

Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.

9.
Bioorg Med Chem Lett ; 25(9): 1905-9, 2015 May 01.
Article in English | MEDLINE | ID: mdl-25857941

ABSTRACT

This Letter describes synthesis, SAR, and biological activity of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides as inhibitors of γ-secretase mediated signaling of Notch receptors. Optimization of this series led to the identification of BMS-871 (compound 30) which displayed robust in vivo efficacy in Notch-dependent leukemia and solid tumor xenograft models.


Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Benzodiazepinones/administration & dosage , Benzodiazepinones/pharmacology , Receptors, Notch/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Benzodiazepinones/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Receptors, Notch/metabolism , Structure-Activity Relationship
10.
J Pharm Sci ; 101(9): 3134-41, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22374830

ABSTRACT

The purpose of this work was to study the permeability of two relatively lipophilic sulfenamide prodrugs of linezolid (clogP 0.85), N-(phenylthio)linezolid (1, clogP 2.77) and N-[(2-ethoxycarbonyl)ethylthio]linezolid (2, clogP 1.43), across Caco-2 cell monolayers. Both prodrugs were found to convert to linezolid in the donor compartment presumably from the reaction with free thiol groups on proteins on the surface of the Caco-2 cells, as no conversion was seen in the donor compartment media per se. Neither of the prodrugs could be detected in the receptor phase from either apical (AP) to basolateral (BL) or BL to AP studies. However, the appearance of linezolid in the receptor phase was biphasic with an initial rapid phase suggesting that the prodrugs were indeed more permeable, and for a short period, some prodrug was able to permeate in competition with conversion to linezolid on the donor phase surface. It appears that the prodrug was able to permeate was rapidly converted to linezolid prior to acceptor phase appearance. The second slower phase was due to the permeability of the donor-phase-formed linezolid, with the slopes similar to those from control experiments with linezolid. The limitations and possible utility of oral sulfenamide prodrugs are discussed.


Subject(s)
Acetamides/metabolism , Intestinal Absorption , Intestinal Mucosa/metabolism , Oxazolidinones/metabolism , Prodrugs/metabolism , Sulfamerazine/metabolism , Acetamides/chemistry , Caco-2 Cells , Humans , Kinetics , Linezolid , Models, Biological , Oxazolidinones/chemistry , Permeability , Prodrugs/chemistry , Sulfamerazine/chemistry
11.
J Med Chem ; 54(20): 7318-33, 2011 Oct 27.
Article in English | MEDLINE | ID: mdl-21899328

ABSTRACT

Structurally novel 5H-chromeno[2,3-b]pyridine (azaxanthene) selective glucocorticoid receptor (GR) modulators have been identified. A screening paradigm utilizing cellular assays of GR-mediated transrepression of proinflammatory transcription factors and transactivation of GR-dependent genes combined with three physiologically relevant assays of cytokine induction in human whole blood has allowed for the identification of high affinity, selective GR ligands that display a broad range of pharmacological profiles. Agonist efficacy in reporter assays can be tuned by halogenation of a pendent phenyl ring and correlates well with efficacy for cytokine inhibition in human whole blood. A hypothetical binding mode is proposed, invoking an expanded ligand binding pocket resembling that of arylpyrazole-bound GR structures. Two compounds of close structural similarity (35 and 37; BMS-776532 and BMS-791826, respectively) have been found to maintain distinct and consistent levels of partial agonist efficacy across several assays, displaying anti-inflammatory activity comparable to that of prednisolone 2 in suppressing cytokine production in whole blood and in rodent models of acute and chronic inflammation.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Receptors, Glucocorticoid/agonists , Thiadiazoles/chemical synthesis , Alkaline Phosphatase/biosynthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Cell Line, Tumor , Drug Partial Agonism , Edema/drug therapy , Glutamate-Ammonia Ligase/biosynthesis , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , In Vitro Techniques , Interleukin-1beta/blood , Male , Models, Molecular , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Response Elements , Stereoisomerism , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/pharmacology , Transcription Factor AP-1/genetics , Transcription Factor AP-1/metabolism , Transcriptional Activation , Tumor Necrosis Factor-alpha/blood , Tyrosine Transaminase/biosynthesis
12.
Bioorg Med Chem Lett ; 21(9): 2780-3, 2011 May 01.
Article in English | MEDLINE | ID: mdl-21513867

ABSTRACT

The objective of this Letter is both to report the permeability results of a linezolid-based sulfenamide prodrug in an MDCK cell model (enterocyte surrogate system) and to discuss the strategic implications of these results for considering sulfenamide prodrugs to enhance the oral delivery of weakly acidic NH-acids (e.g., amides, ureas, etc.). The two main findings from this study are that the sulfenamide prodrug does not appear to survive intracellular transport due to conversion to linezolid and that there appears to be an apically-oriented surface conversion pathway that can additionally serve to convert the sulfenamide prodrug to linezolid upon approach of the apical membrane. It is hoped that these findings, along with the discussion of the strategic implications, will facilitate a greater awareness of the potential strengths and weaknesses inherent in the sulfenamide prodrug approach for enhancing the oral delivery of weakly acidic NH-acid drugs.

13.
Bioorg Med Chem Lett ; 21(1): 172-5, 2011 Jan 01.
Article in English | MEDLINE | ID: mdl-21126873

ABSTRACT

The objective of this Letter is both to report the permeability results of a linezolid-based sulfenamide prodrug in an MDCK cell model (enterocyte surrogate system) and to discuss the strategic implications of these results for considering sulfenamide prodrugs to enhance the oral delivery of weakly acidic NH-acids (e.g., amides, ureas, etc.). The two main findings from this study are that the sulfenamide prodrug does not appear to survive intracellular transport due to conversion to linezolid and that there appears to be an apically-oriented surface conversion pathway that can additionally serve to convert the sulfenamide prodrug to linezolid upon approach of the apical membrane. It is hoped that these findings, along with the discussion of the strategic implications, will facilitate a greater awareness of the potential strengths and weaknesses inherent in the sulfenamide prodrug approach for enhancing the oral delivery of weakly acidic NH-acid drugs.


Subject(s)
Prodrugs/chemistry , Prodrugs/metabolism , Sulfamerazine/chemistry , Sulfamerazine/metabolism , Acids/administration & dosage , Administration, Oral , Animals , Cell Line , Cell Membrane Permeability , Dogs , Prodrugs/chemical synthesis , Sulfamerazine/chemical synthesis
14.
Bioorg Med Chem Lett ; 17(23): 6629-32, 2007 Dec 01.
Article in English | MEDLINE | ID: mdl-17928225

ABSTRACT

Improved synthetic methods are reported for the preparation of sulfenamide derivatives of carbamazepine (CBZ) for evaluation as prodrugs. These sulfenamide prodrugs were designed to rapidly release CBZ in vivo by cleavage of the sulfenamide bond by chemical reaction with glutathione and other sulfhydryl compounds. Physicochemical characterization and in vivo conversion of a new prodrug of CBZ was evaluated to further establish the proof of concept of the sulfenamide prodrug approach.


Subject(s)
Carbamazepine/chemical synthesis , Carbamazepine/metabolism , Prodrugs/chemical synthesis , Prodrugs/metabolism , Sulfamerazine/chemical synthesis , Sulfamerazine/metabolism , Water/chemistry , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/chemical synthesis , Anticonvulsants/metabolism , Carbamazepine/administration & dosage , Glutathione/metabolism , Models, Chemical , Prodrugs/administration & dosage , Rats , Solubility , Sulfamerazine/administration & dosage
15.
Bioorg Med Chem Lett ; 17(17): 4910-3, 2007 Sep 01.
Article in English | MEDLINE | ID: mdl-17604170

ABSTRACT

The objective of this report is to introduce the novel concept of utilizing sulfenamides as prodrugs for compounds containing an NH-acidic functionality, particularly weakly acidic amide-type functionalities (amides, ureas, carbamates, etc.). Included are the syntheses and physicochemical characterizations of some model sulfenamides to illustrate the promise of this new prodrug technology.


Subject(s)
Chemistry, Pharmaceutical/methods , Prodrugs/chemistry , Sulfur/chemistry , Amides/chemistry , Amides/pharmacology , Amines/chemistry , Chemical Phenomena , Chemistry , Drug Design , Hydrogen-Ion Concentration , Hydrolysis , Kinetics , Models, Chemical , Prodrugs/pharmacology , Temperature
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