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1.
J Med Chem ; 62(21): 9931-9946, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31638797

RESUMO

RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.

2.
Bioorg Med Chem Lett ; 29(16): 2265-2269, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31257087

RESUMO

An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.

3.
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.

4.
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 Drogas , 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
5.
Bioorg Med Chem Lett ; 27(4): 855-861, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28108251

RESUMO

As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.


Assuntos
Aminas/química , Inibidores de Proteínas Quinases/química , Aminas/metabolismo , Aminas/uso terapêutico , Animais , Doenças Autoimunes/tratamento farmacológico , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Piperazina , Piperazinas/química , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-Atividade , Triazinas/química
6.
Bioorg Med Chem Lett ; 25(10): 2169-73, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25881820

RESUMO

Heterocyclic amide isosteres were incorporated into a phenylglycine-based tissue factor/factor VIIa (TF-FVIIa) inhibitor chemotype, providing potent inhibitors. An X-ray co-crystal structure of phenylimidazole 19 suggested that an imidazole nitrogen atom effectively mimics an amide carbonyl, while the phenyl ring forms key hydrophobic interactions with the S1' pocket. Exploration of phenylimidazole substitution led to the discovery of potent, selective and efficacious inhibitors of TF-FVIIa.


Assuntos
Desenho de Drogas , Fator VIIa/antagonistas & inibidores , Imidazóis/química , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/farmacologia , Cristalografia por Raios X , Estrutura Molecular , Inibidores de Serino Proteinase/química
7.
Bioorg Med Chem Lett ; 23(18): 5244-8, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23845220

RESUMO

Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P' binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype.


Assuntos
Benzamidinas , Fator VIIa/antagonistas & inibidores , Inibidores de Serino Proteinase/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Fator VIIa/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química
8.
Bioorg Med Chem Lett ; 20(21): 6273-6, 2010 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-20833042

RESUMO

The synthesis and SAR of aminomethyl-substituted imidazolopyrimidine DPP4 inhibitors bearing varied pendant aryl groups is described. Compound 1, which exists as a separable mixture of non-interconvertible atropisomers was used as the starting point for investigation. The effects of substituent pattern and type as well as stereochemical effects on inhibitor potency are discussed.


Assuntos
Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Domínio Catalítico , Dipeptidases/antagonistas & inibidores , Inibidores da Dipeptidil Peptidase IV/química , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Indicadores e Reagentes , Isomerismo , Cinética , Modelos Moleculares , Solventes , Relação Estrutura-Atividade
9.
J Med Chem ; 53(15): 5620-8, 2010 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-20684603

RESUMO

Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.


Assuntos
Inibidores da Dipeptidil Peptidase IV , Hipoglicemiantes/síntese química , Imidazóis/síntese química , Pirimidinas/síntese química , Animais , Domínio Catalítico , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/química , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Imidazóis/farmacocinética , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Obesos , Modelos Moleculares , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Bloqueadores dos Canais de Sódio/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
10.
J Comput Aided Mol Des ; 23(7): 411-8, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19459054

RESUMO

The success of structure-based drug design relies on accurate protein modeling where one of the key issues is the modeling and refinement of loops. This study takes a critical look at modeled loops, determining the effect of re-sampling side-chains after the loop conformation has been generated. The results are evaluated in terms of backbone and side-chain conformations with respect to the native loop. While models can contain loops with high quality backbone conformations, the side-chain orientations could be poor, and therefore unsuitable for ligand docking and structure-based design. In this study, we report on the ability to model loop side-chains accurately using a variety of commercially available algorithms that include rotamer libraries, systematic torsion scans and knowledge-based methods.


Assuntos
Algoritmos , Proteínas/química , Homologia Estrutural de Proteína , Simulação por Computador , Desenho de Drogas , Modelos Moleculares
12.
Protein Sci ; 16(9): 1999-2012, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17660258

RESUMO

This paper provides an unbiased comparison of four commercially available programs for loop sampling, Prime, Modeler, ICM, and Sybyl, each of which uses a different modeling protocol. The study assesses the quality of results and examines the relative strengths and weaknesses of each method. The set of loops to be modeled varied in length from 4-12 amino acids. The approaches used for loop modeling can be classified into two methodologies: ab initio loop generation (Modeler and Prime) and database searches (Sybyl and ICM). Comparison of the modeled loops to the native structures was used to determine the accuracy of each method. All of the protocols returned similar results for short loop lengths (four to six residues), but as loop length increased, the quality of the results varied among the programs. Prime generated loops with RMSDs <2.5 A for loops up to 10 residues, while the other three methods met the 2.5 A criteria at seven-residue loops. Additionally, the ability of the software to utilize disulfide bonds and X-ray crystal packing influenced the quality of the results. In the final analysis, the top-ranking loop from each program was rarely the loop with the lowest RMSD with respect to the native template, revealing a weakness in all programs to correctly rank the modeled loops.


Assuntos
Modelos Moleculares , Oligopeptídeos/química , Estrutura Secundária de Proteína , Software , Algoritmos , Sequência de Aminoácidos , Cristalografia por Raios X , Bases de Dados de Proteínas , Dissulfetos/química , Hidrogênio/química , Concentração de Íons de Hidrogênio , Conformação Proteica
13.
Arch Biochem Biophys ; 445(1): 9-18, 2006 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-16364232

RESUMO

Dipeptidyl peptidase-IV (DPP-IV) is a serine protease with a signature Asp-His-Ser motif at the active site. Our pH data suggest that Gly-Pro-pNA cleavage catalyzed by DPP-IV is facilitated by an ionization of a residue with a pK of 7.2 +/- 0.1. By analogy to other serine proteases this pK is suggestive of His-Asp assisted Ser addition to the P1 carbonyl carbon of the substrate to form a tetrahedral intermediate. Solvent kinetic isotope effect studies yielded a D2Okcat/Km=2.9+/-0.2 and a D2Okcat=1.7+/-0.2 suggesting that kinetically significant proton transfers contribute to rate limitation during acyl intermediate formation (leaving group release) and hydrolysis. A "burst" of product release during pre steady-state Gly-Pro-pNA cleavage indicated rate limitation in the deacylation half-reaction. Nevertheless, the amplitude of the burst exceeded the enzyme concentration significantly (approximately 15-fold), which is consistent with a branching deacylation step. All of these data allowed us to better understand DPP-IV inhibition by saxagliptin (BMS-477118). We propose a two-step inhibition mechanism wherein an initial encounter complex is followed by covalent intermediate formation. Final inhibitory complex assembly (kon) depends upon the ionization of an enzyme residue with a pK of 6.2 +/- 0.1, and we assigned it to the catalytic His-Asp pair which enhances Ser nucleophilicity for covalent addition. An ionization with a pK of 7.9 +/- 0.2 likely reflects the P2 terminal amine of the inhibitor hydrogen bonding to Glu205/Glu206 in the enzyme active site. The formation of the covalent enzyme-inhibitor complex was reversible and dissociated with a koff of (5.5 +/- 0.4) x 10(-5) s(-1), thus yielding a Ki* (as koff/kon) of 0.35 nM, which is in good agreement with the value of 0.6 nM obtained from steady-state inhibition studies. Proton NMR spectra of DPP-IV showed a downfield resonance at 16.1 ppm. Two additional peaks in the 1H NMR spectra at 17.4 and 14.1 ppm were observed upon mixing the enzyme with saxagliptin. Fractionation factors (phi) of 0.6 and 0.5 for the 17.4 and 14.1 ppm peaks, respectively, are suggestive of short strong hydrogen bonds in the enzyme-inhibitor complex.


Assuntos
Adamantano/análogos & derivados , Dipeptídeos/química , Dipeptidil Peptidase 4/química , Inibidores Enzimáticos/química , Adamantano/química , Catálise , Humanos , Concentração de Íons de Hidrogênio , Cinética , Ressonância Magnética Nuclear Biomolecular , Solventes
14.
Bioorg Med Chem Lett ; 14(2): 383-7, 2004 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-14698164

RESUMO

Analogues of isoxazoline alpha(v)beta(3) antagonist 1 designed to further restrict the four carbon alkyl tether were prepared by incorporating two spirocyclic scaffolds, 1-oxa-2-azaspiro[4,5]dec-2-ene and 1-oxa-2,7-diazaspiro[4,4]non-2-ene. Additional optimization provided potent antagonists of both alpha(v)beta(3) and alpha(5)beta(1) which are selective over GPIIb/IIIa.


Assuntos
Imidazóis/síntese química , Integrinas/antagonistas & inibidores , Sítios de Ligação/fisiologia , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Imidazóis/metabolismo , Integrinas/metabolismo , Estereoisomerismo
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