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1.
Bioorg Med Chem Lett ; 35: 127778, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33422603

RESUMO

The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.

2.
Bioorg Med Chem Lett ; 30(19): 127441, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32736080

RESUMO

In an effort to discover oral inverse agonists of RORγt to treat inflammatory diseases, a new 2,6-difluorobenzyl ether series of cyclopentyl sulfones were found to be surprisingly more potent than the corresponding alcohol derivatives. When combined with a more optimized phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone template, the 2,6-difluorobenzyl ethers yielded a set of very potent RORγt inverse agonists (e.g., compound 26, RORγt Gal4 EC50 11 nM) that are highly selective against PXR, LXRα and LXRß. After optimizing for stability in human and mouse liver microsomes, compounds 29 and 38 were evaluated in vivo and found to have good oral bioavailability (56% and 101%, respectively) in mice. X-ray co-crystal structure of compound 27 in RORγt revealed that the bulky benzyl ether group causes helix 11 of the protein to partially uncoil to create a new, enlarged binding site, which nicely accommodates the benzyl ether moiety, leading to net potency gain.

3.
Bioorg Med Chem Lett ; 30(17): 127392, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738966

RESUMO

A novel series of cis-3,4-diphenylpyrrolidines were designed as RORγt inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesis and structure-activity relationship (SAR) study established (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidine as the most effective scaffold. Subsequent SAR optimization led to identification of a piperidinyl carboxamide 31, which was potent against RORγt (EC50 of 61 nM in an inverse agonist assay), selective relative to RORα, RORß, LXRα and LXRß, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Ymax (46%) and emerged as a promising lead. The binding mode of the diphenylpyrrolidine series was established with an X-ray co-crystal structure of 10A/RORγt.

4.
Bioorg Med Chem Lett ; 30(12): 127204, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32334911

RESUMO

Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.

5.
ACS Med Chem Lett ; 10(3): 306-311, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891131

RESUMO

The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.

6.
ACS Med Chem Lett ; 10(3): 367-373, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891142

RESUMO

A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of RORγt inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide 1. Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at N1-position of the pyrrolidine ring and perfluoroisopropyl group at para-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXRα, and LXRß. Further optimization led to the discovery of (1R,4r)-4-((R)-3-((4-fluorophenyl)sulfonyl)-3-(4-(perfluoropropan-2-yl)phenyl)pyrrolidine-1-carbonyl)cyclohexane-1-carboxylic acid (26), which displayed excellent selectivity, desirable liability and pharmacokinetic properties in vitro, and a good pharmacokinetic profile in mouse. Oral administration of 26 demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.

7.
Bioorg Med Chem Lett ; 28(2): 85-93, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29233651

RESUMO

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Desenho de Fármacos , Propanóis/farmacologia , Receptores do Ácido Retinoico/agonistas , Receptores de Esteroides/agonistas , Sulfonamidas/farmacologia , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Receptores X do Fígado/agonistas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Receptor de Pregnano X , Propanóis/síntese química , Propanóis/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
8.
Bioorg Med Chem Lett ; 27(14): 3101-3106, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28539220

RESUMO

A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.


Assuntos
Janus Quinase 1/antagonistas & inibidores , Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridazinas/química , Pirróis/química , Animais , Sítios de Ligação , Domínio Catalítico , Linhagem Celular , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Inflamação/prevenção & controle , Concentração Inibidora 50 , Janus Quinase 1/metabolismo , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Janus Quinase 3/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Conformação Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Piridazinas/síntese química , Piridazinas/farmacocinética , Pirróis/síntese química , Pirróis/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , TYK2 Quinase/antagonistas & inibidores , TYK2 Quinase/metabolismo
9.
Medchemcomm ; 8(11): 2093-2099, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108726

RESUMO

Myeloperoxidase, a mammalian peroxidase involved in the immune system as an anti-microbial first responder, can produce hypochlorous acid in response to invading pathogens. Myeloperoxidase has been implicated in several chronic pathological diseases due to the chronic production of hypochlorous acid, as well as other reactive radical species. A high throughput screen and triaging protocol was developed to identify a reversible inhibitor of myeloperoxidase toward the potential treatment of chronic diseases such as atherosclerosis. The identification and characterization of a reversible myeloperoxidase inhibitor, 7-(benzyloxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine is described.

10.
Bioorg Med Chem Lett ; 26(17): 4256-60, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27476421

RESUMO

Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.


Assuntos
Aminas/química , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Triazinas/química , Aminas/metabolismo , Aminas/uso terapêutico , Animais , Artrite/tratamento farmacológico , Artrite/metabolismo , Artrite/patologia , Sítios de Ligação , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
11.
J Forensic Sci ; 53(1): 100-6, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18279246

RESUMO

Pigments are rapidly replacing dyes as colorants in pen and printer inks, due to their superior colors and stability. Unfortunately, tools commonly used in questioned document examination for analyzing pen inks, such as TLC, cannot be used for the analysis of insoluble pigments on paper. Laser desorption mass spectrometry is demonstrated here as a tool for analyzing pigment-based pen inks. A pulsed nitrogen laser can be focused onto a pen stroke from a pigmented ink pen on paper, and positive and negative ions representative of the pigment can be generated for subsequent mass spectrometric analysis. Targeted pens for this work were a set of Uni-ball 207 pigmented ink pens containing blue, light blue, orange, green, violet, red, pink, and black inks. Copper phthalocyanine was identified as the pigment used to make both blue inks. A mixture of halogenated copper phthalocyanines were identified in the green ink. Unexpectedly, the pink ink was found to contain a red pigment, Pigment Red 12, treated with a mixture of water-soluble dyes. Each sample yielded ions representative of the pigments present.

12.
J Forensic Sci ; 52(3): 595-603, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17456087

RESUMO

When one looks at an automotive coating, one sees color due to pigments. Modern organic pigments, with high molar absorptivities, may be only minor components of the mixture. Laser desorption mass spectrometry (LDMS) has been shown to be a useful tool for the analysis of colorants such as pen ink dyes. Here, LDMS is used to determine its utility for the identification of pigments, in simple media and in more complex paints. Small paint chips can be introduced into the LDMS instrument, and when an ultraviolet laser is focused on a portion of a chip, ions representative of the pigment(s) are selectively formed. Some pigments such as quinacridones and copper phthalocyanine are very stable and are desorbed and ionized intact. In contrast, benzimidazolones, which contain some single-skeletal bonds, form fragment ions. This method proves to be sensitive and convenient, as no sample preparation is required. The presence of inorganic pigments in addition to modern organic pigments can be determined, and pigments can be directly identified in actual automotive paint chip samples.

13.
Langmuir ; 21(9): 4180-4, 2005 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-15835992

RESUMO

This paper reports a robust and efficient approach to assemble highly aligned DNA strands onto Si chips. The method combines advantages from molecular combing and microcontact printing to realize controlling both the density and direction of DNA strands on the Si chip. In addition, it also can be utilized to prepare stretched DNA structures on solid surfaces. Compared to approaches that use molecular combing directly on silanated surfaces, the stretched single-chain DNA structures are straighter. Furthermore, by exploiting the hydrophobic property of the intrinsic poly(dimethylsiloxane) stamp, this study also describes a simple way to produce straight bundled DNA arrays on Si and other substrates.


Assuntos
DNA/química , Nanotecnologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Silício/química , Adsorção , DNA/ultraestrutura , Dimetilpolisiloxanos/química , Interações Hidrofóbicas e Hidrofílicas , Microscopia de Força Atômica , Conformação de Ácido Nucleico , Silicones/química , Propriedades de Superfície
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