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1.
Bioorg Med Chem Lett ; 91: 129373, 2023 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-37315697

RESUMO

Efforts directed at improving potency and preparing structurally different TYK2 JH2 inhibitors from the first generation of compounds such as 1a led to the SAR study of new central pyridyl based analogs 2-4. The current SAR study resulted in the identification of 4h as a potent and selective TYK2 JH2 inhibitor with distinct structural differences from 1a. In this manuscript, the in vitro and in vivo profiles of 4h are described. The hWB IC50 of 4h was shown as 41 nM with 94% bioavailability in the mouse PK study.


Assuntos
Piridinas , TYK2 Quinase , Camundongos , Animais , Relação Estrutura-Atividade , Piridinas/farmacologia
2.
J Med Chem ; 64(3): 1454-1480, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33492963

RESUMO

Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P1-5). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P1 has been shown to result in lymphopenia. As a result, agonists of this type hold promise as therapeutics for autoimmune disorders. The previously disclosed differentiated S1P1 modulator BMS-986104 (1) exhibited improved preclinical cardiovascular and pulmonary safety profiles as compared to earlier full agonists of S1P1; however, it demonstrated a long pharmacokinetic half-life (T1/2 18 days) in the clinic and limited formation of the desired active phosphate metabolite. Optimization of this series through incorporation of olefins, ethers, thioethers, and glycols into the alkyl side chain afforded an opportunity to reduce the projected human T1/2 and improve the formation of the active phosphate metabolite while maintaining efficacy as well as the improved safety profile. These efforts led to the discovery of 12 and 24, each of which are highly potent, biased agonists of S1P1. These compounds not only exhibited shorter in vivo T1/2 in multiple species but are also projected to have significantly shorter T1/2 values in humans when compared to our first clinical candidate. In models of arthritis, treatment with 12 and 24 demonstrated robust efficacy.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Pró-Proteína Convertases/efeitos dos fármacos , Serina Endopeptidases/efeitos dos fármacos , Animais , Artrite Experimental/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Biotransformação , Compostos Bicíclicos com Pontes/efeitos adversos , Líquido da Lavagem Broncoalveolar , Quimiotaxia de Leucócito/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Pneumopatias/induzido quimicamente , Pneumopatias/patologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Fosforilação , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade
3.
ACS Med Chem Lett ; 11(9): 1766-1772, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32944145

RESUMO

Efforts aimed at increasing the in vivo potency and reducing the elimination half-life of 1 and 2 led to the identification of aryl ether and thioether-derived bicyclic S1P1 differentiated modulators 3-6. The effects of analogs 3-6 on lymphocyte reduction in the rat (desired pharmacology) along with pulmonary- and cardiovascular-related effects (undesired pharmacology) are described. Optimization of the overall properties in the aryl ether series yielded 3d, and the predicted margin of safety against the cardiovascular effects of 3d would be large enough for human studies. Importantly, compared to 1 and 2, compound 3d had a better profile in both potency (ED50 < 0.05 mg/kg) and predicted human half-life (t 1/2 ∼ 5 days).

4.
J Med Chem ; 62(5): 2265-2285, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30785748

RESUMO

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.


Assuntos
Ensaios Clínicos como Assunto , Naftalenos/farmacologia , Receptores de Esfingosina-1-Fosfato/agonistas , Tetra-Hidronaftalenos/farmacologia , Animais , Líquido da Lavagem Broncoalveolar , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Naftalenos/química , Naftalenos/farmacocinética , Ratos , Ratos Endogâmicos Lew , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacocinética
5.
J Med Chem ; 59(24): 11138-11147, 2016 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-28002964

RESUMO

We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient approach to prepare this class of compounds. In addition, we disclose the efficacy of 4a in a mouse EAE model, which is comparable to 4c (FTY720). Mechanistically, 4a exhibited excellent remyelinating effects on lysophosphatidylcholine (LPC) induced demyelination in a three-dimensional brain cell culture assay.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Naftalenos/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Humanos , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Relação Estrutura-Atividade
6.
J Med Chem ; 59(21): 9837-9854, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27726358

RESUMO

Fingolimod (1) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a nonselective S1P receptor agonist, agonism specifically of S1P1 is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P1 while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand-based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P1 with selectivity over S1P3 and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes. Compound 10 had the desired pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated maximal efficacy when administered orally in a rat adjuvant arthritis model.


Assuntos
Desenho de Fármacos , Cloridrato de Fingolimode/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Cães , Relação Dose-Resposta a Droga , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/química , Adjuvante de Freund/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/química , Ligantes , Linfócitos/efeitos dos fármacos , Macaca fascicularis , Masculino , Camundongos , Estrutura Molecular , Mycobacterium/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Distribuição Tecidual
7.
J Med Chem ; 59(13): 6248-64, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27309907

RESUMO

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates a multitude of physiological processes such as lymphocyte trafficking, cardiac function, vascular development, and inflammation. Because of the ability of S1P1 receptor agonists to suppress lymphocyte egress, they have great potential as therapeutic agents in a variety of autoimmune diseases. In this article, the discovery of selective, direct acting S1P1 agonists utilizing an ethanolamine scaffold containing a terminal carboxylic acid is described. Potent S1P1 agonists such as compounds 18a and 19a which have greater than 1000-fold selectivity over S1P3 are described. These compounds efficiently reduce blood lymphocyte counts in rats through 24 h after single doses of 1 and 0.3 mpk, respectively. Pharmacodynamic properties of both compounds are discussed. Compound 19a was further studied in two preclinical models of disease, exhibiting good efficacy in both the rat adjuvant arthritis model (AA) and the mouse experimental autoimmune encephalomyelitis model (EAE).


Assuntos
Etanolamina/química , Etanolamina/farmacologia , Linfócitos/efeitos dos fármacos , Receptores de Lisoesfingolipídeo/agonistas , Animais , Artrite/tratamento farmacológico , Cães , Encefalomielite Autoimune Experimental/tratamento farmacológico , Etanolamina/farmacocinética , Etanolamina/uso terapêutico , Feminino , Haplorrinos , Humanos , Contagem de Linfócitos , Linfócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos Lew , Receptores de Lisoesfingolipídeo/metabolismo , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 23(19): 5442-7, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23953070

RESUMO

Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.


Assuntos
Amidas/química , Amidas/farmacologia , Descoberta de Drogas , Receptores de Glucocorticoides/agonistas , Sítios de Ligação , Cristalografia por Raios X , Humanos , Indazóis/química , Indazóis/farmacologia , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Esteroides/química , Esteroides/farmacologia , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 23(19): 5448-51, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23916594

RESUMO

SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors.


Assuntos
Indazóis/síntese química , Indazóis/farmacologia , Receptores de Glucocorticoides/agonistas , Amidas/química , Amidas/farmacologia , Humanos , Indazóis/química , Modelos Moleculares , Ligação Proteica/efeitos dos fármacos , Receptores de Glucocorticoides/química , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Ureia/química , Ureia/farmacologia
10.
Bioorg Med Chem Lett ; 17(16): 4678-82, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17576061

RESUMO

A novel series of TNF-alpha converting enzyme (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds use a triazolethione moiety as the zinc binding ligand and exhibit IC50 values from 1.5 to 100 nM in a porcine TACE assay. They also have excellent selectivities over other MMPs.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Proteína ADAM17 , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Compostos Heterocíclicos/química , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 17(10): 2769-74, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17368021

RESUMO

We have discovered selective and potent inhibitors of TACE that replace the common hydroxamate zinc binding group with a hydantoin, triazolone, and imidazolone heterocycle. These novel heterocyclic inhibitors of a zinc metalloprotease were designed using a pharmacophore model that we previously described while developing hydantoin and pyrimidinetrione (barbiturate) inhibitors of TACE. The potency and binding orientation of these inhibitors is discussed and they are modeled into the X-ray crystal structure of TACE and compared to hydroxamate and earlier hydantoin TACE inhibitors which share the same 4-[(2-methyl-4-quinolinyl)methoxy]benzoyl P1' group.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Hidantoínas/farmacologia , Imidazóis/farmacologia , Triazóis/farmacologia , Proteína ADAM17 , Inibidores Enzimáticos/química , Hidantoínas/química , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Triazóis/química
12.
Bioorg Med Chem Lett ; 17(5): 1408-12, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17188861

RESUMO

Recently, an X-ray co-crystal structure of our hydroxamate inhibitor IK682 and TACE [Niu, X.; Umland, S.; Ingram, R.; Beyer, B. M.; Liu, Y.-H.; Sun, J.; Lundell, D.; Orth, P. Arch. Biochem. Biophys. 2006, 451, 43-50] was published that explicitly shows the orientation of the hydroxamate and the TACE-selective 4-[(2-methyl-4-quinolinyl)methoxy]phenyl P1' group in the S1' and S3' sites. The preceding paper described a novel series of potent and TACE-selective hydantoins and we previously described pyrimidinetrione (barbiturate) inhibitors of TACE, both of which contain the same P1' group as IK682. Using this TACE-selective P1' group as an anchor, stereochemical and conformational constraints in the inhibitors, and restrictions to the active site Zn coordination geometry, we developed a highly plausible and predictive pharmacophore model that rationalizes the observed TACE activity of all three inhibitors.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Modelos Moleculares , Proteínas ADAM/química , Proteína ADAM17 , Sítios de Ligação , Humanos , Hidantoínas/química , Hidantoínas/farmacologia , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Lactamas/química , Lactamas/farmacologia , Conformação Molecular , Pirimidinonas/química , Pirimidinonas/farmacologia , Relação Estrutura-Atividade , Zinco/química
13.
Bioorg Med Chem Lett ; 17(5): 1413-7, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17188863

RESUMO

A series of novel hydantoins was designed and synthesized as structural alternatives to hydroxamate inhibitors of TACE. 5-Mono- and di-substituted hydantoins exhibited activity with IC50 values of 11-60 nM against porcine TACE in vitro and excellent selectivity against other MMPs.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Hidantoínas/síntese química , Hidantoínas/farmacologia , Proteína ADAM17 , Animais , Desenho de Fármacos , Concentração Inibidora 50 , Relação Estrutura-Atividade , Especificidade por Substrato , Suínos
14.
Bioorg Med Chem Lett ; 16(10): 2699-704, 2006 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-16516466

RESUMO

A novel series of achiral TNF-alpha converting enzyme (TACE) inhibitors has been discovered. These compounds exhibited activities from 0.35 to 11nM in a porcine TACE assay and inhibited TNF-alpha production in an LPS-stimulated whole blood assay with an IC(50) value of 23nM for the most potent one. They also have excellent selectivities over related metalloproteases including aggrecanases.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Proteína ADAM17 , Animais , Linhagem Celular , Ciclização , Humanos , Camundongos , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Estereoisomerismo , Relação Estrutura-Atividade
15.
Bioorg Med Chem Lett ; 16(4): 1028-31, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16289878

RESUMO

Novel sultam hydroxamates with potent MMP activity were transformed into potent TACE inhibitors, lacking MMP activity. To accomplish this we relied on structural differences between the MMP and TACE S1' pockets and the known advantageous fit of a 2-methyl-4-quinolinylmethoxyphenyl group into this region. From this approach, compound 7d was identified as a potent TACE inhibitor (IC50 = 3.7 nM) that lacked MMP-1, -2, -9, and -13 activity.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores Enzimáticos , Ácidos Hidroxâmicos , Metaloproteases/antagonistas & inibidores , Sulfonamidas , Proteína ADAM17 , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
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