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1.
J Med Chem ; 63(23): 15050-15071, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33261314

RESUMO

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.

2.
Bioorg Med Chem Lett ; 30(21): 127495, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32798651

RESUMO

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.

3.
Bioorg Med Chem Lett ; 30(3): 126856, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31870650

RESUMO

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.

4.
J Med Chem ; 62(16): 7400-7416, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31246024

RESUMO

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.


Assuntos
Benzofuranos/farmacologia , Fibrinolíticos/farmacologia , Hemorragia/prevenção & controle , Receptores de Trombina/antagonistas & inibidores , Trombose/prevenção & controle , Animais , Benzofuranos/química , Benzofuranos/farmacocinética , Disponibilidade Biológica , Modelos Animais de Doenças , Fibrinolíticos/química , Fibrinolíticos/farmacocinética , Células HEK293 , Hemorragia/metabolismo , Humanos , Macaca fascicularis , Modelos Químicos , Estrutura Molecular , Agregação Plaquetária/efeitos dos fármacos , Receptores de Trombina/genética , Receptores de Trombina/metabolismo , Relação Estrutura-Atividade , Trombose/metabolismo
5.
J Pharm Sci ; 101(9): 3134-41, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22374830

RESUMO

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.


Assuntos
Acetamidas/metabolismo , Absorção Intestinal , Mucosa Intestinal/metabolismo , Oxazolidinonas/metabolismo , Pró-Fármacos/metabolismo , Sulfamerazina/metabolismo , Acetamidas/química , Células CACO-2 , Humanos , Cinética , Linezolida , Modelos Biológicos , Oxazolidinonas/química , Permeabilidade , Pró-Fármacos/química , Sulfamerazina/química
6.
Bioorg Med Chem Lett ; 21(9): 2780-3, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21513867

RESUMO

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.

7.
Bioorg Med Chem Lett ; 21(1): 172-5, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21126873

RESUMO

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.


Assuntos
Pró-Fármacos/química , Pró-Fármacos/metabolismo , Sulfamerazina/química , Sulfamerazina/metabolismo , Ácidos/administração & dosagem , Administração Oral , Animais , Linhagem Celular , Permeabilidade da Membrana Celular , Cães , Pró-Fármacos/síntese química , Sulfamerazina/síntese química
8.
Bioorg Med Chem Lett ; 17(23): 6629-32, 2007 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-17928225

RESUMO

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.


Assuntos
Carbamazepina/síntese química , Carbamazepina/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Sulfamerazina/síntese química , Sulfamerazina/metabolismo , Água/química , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/síntese química , Anticonvulsivantes/metabolismo , Carbamazepina/administração & dosagem , Glutationa/metabolismo , Modelos Químicos , Pró-Fármacos/administração & dosagem , Ratos , Solubilidade , Sulfamerazina/administração & dosagem
9.
Bioorg Med Chem Lett ; 17(17): 4910-3, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17604170

RESUMO

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.


Assuntos
Química Farmacêutica/métodos , Pró-Fármacos/química , Enxofre/química , Amidas/química , Amidas/farmacologia , Aminas/química , Fenômenos Químicos , Química , Desenho de Fármacos , Concentração de Íons de Hidrogênio , Hidrólise , Cinética , Modelos Químicos , Pró-Fármacos/farmacologia , Temperatura
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