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1.
J Org Chem ; 86(2): 1730-1747, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33356273

RESUMO

Indole and indoline rings are important pharmacophoric scaffolds found in marketed drugs, agrochemicals, and biologically active molecules. The [2 + 2] cycloaddition reaction is a versatile strategy for constructing architecturally interesting, sp3-rich cyclobutane-fused scaffolds with potential applications in drug discovery programs. A general platform for visible-light mediated intermolecular [2 + 2] cycloaddition of indoles with alkenes has been realized. A substrate-based screening approach led to the discovery of tert-butyloxycarbonyl (Boc)-protected indole-2-carboxyesters as suitable motifs for the intermolecular [2 + 2] cycloaddition reaction. Significantly, the reaction proceeds in good yield with a wide variety of both activated and unactivated alkenes, including those containing free amines and alcohols, and the transformation exhibits excellent regio- and diastereoselectivity. Moreover, the scope of the indole substrate is very broad, extending to previously unexplored azaindole heterocycles that collectively afford fused cyclobutane containing scaffolds that offer unique properties with functional handles and vectors suitable for further derivatization. DFT computational studies provide insights into the mechanism of this [2 + 2] cycloaddition, which is initiated by a triplet-triplet energy transfer process. The photocatalytic reaction was successfully performed on a 100 g scale to provide the dihydroindole analog.

2.
ACS Med Chem Lett ; 11(11): 2195-2203, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33214829

RESUMO

Bruton's tyrosine kinase (BTK) has been shown to play a key role in the pathogenesis of autoimmunity. Therefore, the inhibition of the kinase activity of BTK with a small molecule inhibitor could offer a breakthrough in the clinical treatment of many autoimmune diseases. This Letter describes the discovery of BMS-986143 through systematic structure-activity relationship (SAR) development. This compound benefits from defined chirality derived from two rotationally stable atropisomeric axes, providing a potent and selective single atropisomer with desirable efficacy and tolerability profiles.

3.
J Org Chem ; 85(16): 10988-10993, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32687358

RESUMO

We describe an efficient synthetic route to differentially protected diester, 1-(tert-butyl) 4-methyl (1R,2S,4R)-2-methylcyclohexane-1,4-dicarboxylate (+)-1, via palladium-catalyzed methoxycarbonylation of an enol triflate derived from a Hagemann's ester derivative followed by a stereoselective Crabtree hydrogenation. Diester 1 is a novel chiral synthon useful in drug discovery and was instrumental in the generation of useful SAR during a RORγt inverse agonist program. In addition, we describe a second-generation synthesis of the clinical candidate BMS-986251, using diester 1 as a critical component.

4.
J Am Chem Soc ; 142(6): 3094-3103, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-31927959

RESUMO

We describe the synthesis through visible-light photocatalysis of novel functionalized tetracyclic scaffolds that incorporate a fused azabicyclo[3.2.0]heptan-2-one motif, which are structurally interesting cores with potential in natural product synthesis and drug discovery. The synthetic approach involves an intramolecular [2 + 2] cycloaddition with concomitant dearomatization of the heterocycle via an energy transfer process promoted by an iridium-based photosensitizer, to build a complex molecular architecture with at least three stereogenic centers from relatively simple, achiral precursors. These fused azabicyclo[3.2.0]heptan-2-one-based tetracycles were obtained in high yield (generally >99%) and with excellent diastereoselectivity (>99:1). The late-stage derivatization of a bromine-substituted, tetracyclic indoline derivative with alkyl groups, employing a mild Negishi C-C bond forming protocol as a means of increasing structural diversity, provides additional modularity that will enable the delivery of valuable building blocks for medicinal chemistry. Density functional theory calculations were used to compute the T1-S0 free energy gap of the olefin-tethered precursors and also to predict their reactivities based on triplet state energy transfer and transition state energy feasibility.

5.
J Med Chem ; 62(20): 8973-8995, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31318208

RESUMO

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Descoberta de Drogas , Compostos Heterocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Animais , Cristalografia por Raios X , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Compostos Heterocíclicos/uso terapêutico , Humanos , Camundongos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico
6.
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.

7.
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.
Bioorg Med Chem Lett ; 27(21): 4908-4913, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28947151

RESUMO

The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.


Assuntos
Desenho de Fármacos , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Niacinamida/química , Inibidores de Proteínas Quinases/química , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Janus Quinase 3/química , Janus Quinase 3/metabolismo , Conformação Molecular , Simulação de Dinâmica Molecular , Niacinamida/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
10.
J Pharmacol Exp Ther ; 363(3): 377-393, 2017 12.
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
11.
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
12.
J Pharm Biomed Anal ; 131: 54-63, 2016 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-27522108

RESUMO

A series of racemic 2,2-dimethyl-3-aryl-propanoic acids were resolved by chiral supercritical fluid chromatography (SFC) without the use of an acidic additive, trifluoroacetic acid (TFA). The use of additive-free protic methanol as co-solvent in CO2 was expanded to successfully resolve other series of carboxylic acid containing racemates. Large-scale SFC of racemic acid 4, 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid, in methanol without TFA as additive on both Chiralpak AD-H and Chiralcel OJ-H will be discussed, along with impact on throughput and solvent consumption. Investigation of co-solvent effect on peak sharpening of acid racemate 20, 2-(2-chloro-9-fluoro-5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanoic acid, without TFA further indicated that methanol in CO2 provided improved peak shape compared with isopropanol (IPA) and acetonitrile. Finally, we discuss the resolution of basic aromatic chiral amines without the addition of basic additives such as diethylamine (DEA) and application of this protocol for the large-scale SFC separation of weakly basic indazole-containing racemate 14, methyl 3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate, in methanol without DEA.


Assuntos
Cromatografia com Fluido Supercrítico/métodos , Ácidos Pentanoicos/análise , Ácidos Pentanoicos/química
13.
Bioorg Med Chem Lett ; 26(10): 2470-2474, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27055941

RESUMO

The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Relação Estrutura-Atividade , Administração Oral , Animais , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Contagem de Linfócitos , Masculino , Ratos Endogâmicos Lew , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/agonistas
14.
ACS Med Chem Lett ; 6(8): 845-9, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288682

RESUMO

Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

15.
Bioorg Med Chem Lett ; 21(23): 7006-12, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22018461

RESUMO

The synthesis, structure-activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease.


Assuntos
Acetamidas/química , Descoberta de Drogas , Inibidores Enzimáticos/química , Compostos Heterocíclicos com 3 Anéis/química , Quinase I-kappa B/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/farmacologia , Administração Oral , Animais , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
17.
J Pharmacol Exp Ther ; 331(2): 349-60, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19652024

RESUMO

We have previously shown that inhibitors of IkappaB kinase beta (IKKbeta), including 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline (BMS-345541), are efficacious against experimental arthritis in rodents. In our efforts to identify an analog as a clinical candidate for the treatment of autoimmune and inflammatory disorders, we have discovered the potent and highly selective IKKbeta inhibitor 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066). Investigations of its pharmacology in rodent models of experimental arthritis showed that BMS-066 at doses of 5 and 10 mg/kg once daily was effective at protecting rats against adjuvant-induced arthritis, despite showing only weak inhibition at 10 mg/kg against a pharmacodymanic model of tumor necrosis factor alpha production in rats challenged with lipopolysaccharide. The duration of exposure in rats indicated that just 6 to 9 h of coverage per day of the concentration necessary to inhibit IKKbeta by 50% in vivo was necessary for protection against arthritis. Similar findings were observed in the mouse collagen-induced arthritis model, with efficacy observed at a dose providing only 6 h of coverage per day of the concentration necessary to inhibit IKKbeta by 50%. This finding probably results from the cumulative effect on multiple cellular mechanisms that contribute to autoimmunity and joint destruction, because BMS-066 was shown to inhibit a broad spectrum of activities such as T cell proliferation, B cell function, cytokine and interleukin secretion from monocytes, T(H)17 cell function and regulation, and osteoclastogenesis. Thus, only partial and transient inhibition of IKKbeta is sufficient to yield dramatic benefit in vivo, and this understanding will be important in the clinical development of IKKbeta inhibitors.


Assuntos
Acetamidas/farmacologia , Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Acetamidas/farmacocinética , Acetamidas/uso terapêutico , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/patologia , Autoimunidade/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Proteínas I-kappa B/metabolismo , Imunoglobulinas/biossíntese , Técnicas In Vitro , Articulações/patologia , Células Jurkat , Lipopolissacarídeos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Ligação Proteica , Ratos , Ratos Endogâmicos Lew , Fator de Necrose Tumoral alfa/biossíntese
20.
J Med Chem ; 52(7): 1994-2005, 2009 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-19267461

RESUMO

The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IkappaB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.


Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Quinase I-kappa B/antagonistas & inibidores , Imidazóis/síntese química , Oxazóis/síntese química , Tiazóis/síntese química , Animais , Cristalografia por Raios X , Feminino , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Quinase I-kappa B/genética , Imidazóis/farmacocinética , Imidazóis/farmacologia , Técnicas In Vitro , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Oxazóis/farmacocinética , Oxazóis/farmacologia , Ratos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Fator de Necrose Tumoral alfa/biossíntese
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