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1.
Bioorg Med Chem Lett ; : 126782, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31767265

RESUMO

Uncialamycin is one of the structurally simpler and newer members of enediyne family of natural products. It exhibits highly potent activity against several types of bacteria and cancer cells. Described herein is a strategy for the targeted delivery of this cytotoxic agent to tumors using an antibody-drug conjugate (ADC) approach. Central to the design of ADC were the generation of potent and chemically stable uncialamycin analogues and attachment of protease cleavable linkers to newly realized phenolic handles to prepare linker-payloads. Conjugation of the linker-payloads to tumor targeting antibody, in vitro activity and in vivo evaluation are presented.

2.
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.

3.
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.

4.
J Med Chem ; 62(7): 3228-3250, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30893553

RESUMO

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.

5.
J Med Chem ; 62(5): 2265-2285, 2019 Mar 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.

6.
J Chromatogr A ; 1586: 106-115, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30578026

RESUMO

Bruton's tyrosine kinase (BTK) plays an essential role in multiple cell types responsible for numerous autoimmune diseases, thus inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases. Preparative-scale super/subcritical fluid chromatography (SFC) separation methods for four groups of highly potent and selective BTK inhibitor atropisomers were successfully developed. Depending on the rotation barrier around the chiral axis, the compounds were prepared as a single stereochemically stable atropisomer or as an atropisomeric mixture. Among the four, compound 2 with one rotationally stable atropisomeric center (carbazole/quinazolinedione based) was resolved as a mixture of two atropisomers, while compound 3 (carbazole-chlorine/quinazolinedione based) and 4 (tetrahydrocarbazole-fluorine/quinazolinedione based) with two rotationally stable atropisomeric centers were resolved into a single stable atropisomer. This article discusses the challenges and strategies in preparing large quantities of these atropisomeric active pharmaceutical ingredients (APIs) in support of the BTK program discovery efforts.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Cromatografia com Fluido Supercrítico/métodos , Descoberta de Drogas/métodos , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/isolamento & purificação , Descoberta de Drogas/instrumentação , Humanos , Estereoisomerismo
7.
J Assoc Physicians India ; 66(3): 18-21, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30341862

RESUMO

Introduction: Vitamin D deficiency is highly prevalent condition in western countries as well as in India. Lower level of vitamin D is associated with increased arterial stiffness by activating renin-angiotensin-aldosterone system leading to increased cardiovascular morbidity and mortality including increased risk of coronary artery disease, stroke, peripheral vascular disease, hypertension, diabetes mellitus and metabolic syndrome. Our aim was to study the correlation between serum vitamin D level, various measures of arterial stiffness and cardiovascular morbidity in elderly individuals. Material and Method: The present study was conducted in collaboration with Department of Medicine, Department of Cardiology and Regional Geriatric Centre, NPHCE, MDM Hospital attached to Dr. S.N. medical college Jodhpur. Total 100 elderly individuals 60 yrs and above attending hospital for minor short illness, acute illness or for routine health checkup or with acute coronary events are included in the study. Vitamin D level was assessed by chemiluminescent immunoassay. Pulse Wave Velocity was determined by Periscope. Results: In subjects with coronary artery disease, 28.30% were vitamin D deficient, 49.05% were vitamin D insufficient and only 22.64% are vitamin D sufficient. In healthy subjects, 25.53% were vitamin D deficient, 23.40% were vitamin D insufficient and 51.04% were vitamin D sufficient. The difference between these groups was statistically highly significant. (p value-0.006). Various measures of arterial stiffness including Rt baPWV, Lt baPWV, cf PWV and pulse pressure are more in vitamin D deficient group as compared to vitamin D sufficient group. The difference was statistically significant. Conclusion: Vitamin D deficiency is quite common condition in elderly individuals which besides its bone mineralization action is also involved in cardiovascular functions. Deficiency of vitamin D may cause increase in arterial stiffness and widening of pulse pressure which are the predictor of atherosclerosis and cardiovascular morbidity and mortality.

8.
ACS Med Chem Lett ; 9(5): 472-477, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29795762

RESUMO

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.

9.
ACS Med Chem Lett ; 9(2): 143-148, 2018 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-29456803

RESUMO

The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of 18 with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C-H of the CHF2 moiety and the backbone carbonyl of Leu135 of the enzyme. Structure-activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH3 and CF3 analogues, respectively, providing insight into the deployment of this unique amino acid.

10.
J Med Chem ; 61(3): 681-694, 2018 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-29316397

RESUMO

G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.

11.
J Chromatogr A ; 1531: 122-130, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29174572

RESUMO

Analysis and purification of boronic acid pinacol esters by RPLC is very challenging due to their degradation in aqueous and alcoholic solvents. These compounds are difficult to purify by SFC too as they are equally sensitive to traditional co-solvents like methanol, ethanol, and 2-propanol. 2,2,2 trifluoroethanol (TFE), which has been reported for the purification of a few alcohol sensitive compounds, was evaluated as a co-solvent in this study for the purification of chiral and achiral boronate esters by SFC. Examples of twelve compounds were presented in this paper where degradation of boronic acid pinacol esters was successfully controlled by replacing methanol with TFE as the co-solvent in SFC. A separate study showed that TFE can also control the epimerization of the enantiomers of 3 substituted 1,4 benzodiazepine analogues during the purification process. In addition to above benefits, 2,2,2trifloroethanol showed improved selectivity and resolution for most of the compounds. With its stronger solvent strength compared to other alcohols, TFE could also be used to reduce the co-solvent percentage needed for elution and to shorten retention time of highly polar samples which did not elute even in 50% of other co-solvents in SFC. A case study of compound B demonstrated that TFE provided a reduced co-solvent percentage and a shorter cycle time with much improved resolution as compared to methanol, thus resulting in higher loading and throughput with reduction of total solvent consumption.


Assuntos
Ácidos Borônicos/química , Cromatografia com Fluido Supercrítico/métodos , Ésteres/isolamento & purificação , Solventes/química , Trifluoretanol/química , Ésteres/química , Metanol/química , Estereoisomerismo
12.
J Med Chem ; 60(23): 9703-9723, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29077405

RESUMO

Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa Ki = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.


Assuntos
Anticoagulantes/química , Anticoagulantes/uso terapêutico , Fator XIa/antagonistas & inibidores , Isoquinolinas/química , Isoquinolinas/uso terapêutico , Trombose/tratamento farmacológico , para-Aminobenzoatos/química , para-Aminobenzoatos/uso terapêutico , Animais , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Cristalografia por Raios X , Cães , Descoberta de Drogas , Fator XIa/química , Fator XIa/metabolismo , Humanos , Isoquinolinas/farmacocinética , Isoquinolinas/farmacologia , Masculino , Simulação de Acoplamento Molecular , Coelhos , Ratos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Trombose/sangue , para-Aminobenzoatos/farmacocinética , para-Aminobenzoatos/farmacologia
14.
J Org Chem ; 82(19): 10376-10387, 2017 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-28877441

RESUMO

An efficient large-scale synthesis of acid 1, a penultimate precursor to the HCV NS5A inhibitor BMS-986097, along with the final API step are described. Three routes were devised for the synthesis of 1 at the various stages of the program. The third generation route, the one that proved scalable and is the main subject of this paper, features a one-step Michael addition of t-butyl 2-((diphenylmethylene)amino)acetate (24) to (E)-benzyl 4-(1-hydroxycyclopropyl)but-2-enoate (28) followed by cyclization and chiral separation to form 27c, the core skeleton of cap piece 1. The epimerization and chiral resolution of 27c followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran 1. A detailed study of diphenylmethane deprotection via acid hydrolysis as well as a key lactone to tetrahydropyran conversion, in order to avoid a side reaction that afforded an alternative cyclization product, are discussed. This synthesis was applied to the preparation of more than 100 g of the final API BMS-986097 for toxicology studies.


Assuntos
Antivirais/síntese química , Glicina/análogos & derivados , Imidazóis/síntese química , Piranos/farmacologia , Pirrolidinas/síntese química , Compostos de Espiro/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Estrutura Molecular , Piranos/síntese química , Piranos/química , Pirrolidinas/química , Pirrolidinas/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Proteínas não Estruturais Virais/metabolismo
15.
J Pharmacol Exp Ther ; 363(3): 377-393, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28954811

RESUMO

(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 µM) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Organofosfatos/uso terapêutico , Piperidinas/uso terapêutico , Pró-Fármacos/uso terapêutico , Pirrolidinonas/uso terapêutico , Receptores de N-Metil-D-Aspartato/metabolismo , Administração Intravenosa , Regulação Alostérica , Animais , Antidepressivos/efeitos adversos , Antidepressivos/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Ondas Encefálicas/efeitos dos fármacos , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/psicologia , Transtornos Dissociativos/induzido quimicamente , Macaca fascicularis , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Organofosfatos/efeitos adversos , Organofosfatos/farmacocinética , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacocinética , Ensaio Radioligante , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Xenopus
16.
J Chromatogr A ; 1511: 101-106, 2017 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-28687240

RESUMO

Purification of many pharmaceutical compounds by supercritical fluid chromatography (SFC) has always been challenging because of degradation of compound during the isolation step in the presence of acidic or basic modifiers in the mobile phase. Stability of such acid or base-sensitive compounds could be improved by post-column addition of a solvent containing base or acid modifier as counter ion through a make-up pump respectively to neutralize the compound fraction without affecting the resolution. One such case study has been presented in this work where the stability of a base-sensitive compound was addressed by the addition of acidic co-solvent through the make-up pump. Details of this setup and the investigation of degradation of the in-house base-sensitive compound are discussed in this paper. In addition, poor retentivity and low recovery of many non-polar compounds in SFC eluting under low co-solvent percentage is another major concern. Even though the desired separation could be achieved with low percentage of co-solvent, it's difficult to get the proper recovery after purification due to precipitation of the sample and significant aerosol formation inside the cyclone. We have demonstrated the first-time use of a post-column make-up pump on SFC 350 system to introduce additional solvent prior to cyclone to avoid the precipitation, reduce the aerosol formation and thus improve the recovery of non-polar compounds eluting under less than 10% of co-solvent.


Assuntos
Cromatografia com Fluido Supercrítico/métodos , Dióxido de Carbono/química , Dioxolanos/análise , Furanos/análise , Ácidos Mandélicos/análise , Mianserina/análise , Preparações Farmacêuticas/análise , Solventes/química , Estereoisomerismo
17.
Bioorg Med Chem Lett ; 27(15): 3294-3300, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28633899

RESUMO

The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as XimencyTM.


Assuntos
Antivirais/química , Antivirais/farmacologia , Benzazepinas/química , Benzazepinas/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Benzazepinas/farmacocinética , Cães , Haplorrinos , Hepacivirus/enzimologia , Hepacivirus/metabolismo , Hepatite C/virologia , Humanos , RNA Replicase/antagonistas & inibidores , RNA Replicase/metabolismo , Ratos , Proteínas não Estruturais Virais/metabolismo
18.
J Med Chem ; 60(12): 5193-5208, 2017 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-28541707

RESUMO

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.


Assuntos
Artrite Experimental/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Relação Estrutura-Atividade , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Células CACO-2/efeitos dos fármacos , Células CACO-2/imunologia , Cães , Canal de Potássio ERG1/metabolismo , Inibidores Enzimáticos/química , Feminino , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Coelhos
19.
J Med Chem ; 60(9): 3795-3803, 2017 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-28418664

RESUMO

We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , Quinazolinas/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cães , Espectrometria de Massas , Bloqueadores dos Canais de Potássio/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Quinazolinas/química , Quinazolinas/farmacologia , Coelhos , Bloqueadores dos Canais de Sódio/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
20.
J Med Chem ; 60(4): 1417-1431, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28112924

RESUMO

A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding Ki and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both Gq-coupled intracellular Ca2+ flux and Gs-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.


Assuntos
Hipoglicemiantes/farmacologia , Pirrolidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Glicemia/análise , Glicemia/metabolismo , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Ratos , Receptores Acoplados a Proteínas-G/metabolismo
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