RESUMO
Screening of 100 acylsulfonamides from the Bristol-Myers Squibb compound collection identified the C3-cyclohexyl indole 6 as a potent Nav1.7 inhibitor. Replacement of the C2 furanyl ring of 6 with a heteroaryl moiety or truncation of this group led to the identification of 4 analogs with hNav1.7 IC50 values under 50â¯nM. Fluorine substitution of the truncated compound 12 led to 34 with improved potency and isoform selectivity. The inverted indole 36 also maintained good activity. Both 34 and 36 exhibited favorable CYP inhibition profiles, good membrane permeability and a low efflux ratio and, therefore, represent new leads in the search for potent and selective Nav1.7 inhibitors to treat pain.
Assuntos
Descoberta de Drogas , Indóis/química , Canal de Sódio Disparado por Voltagem NAV1.7/efeitos dos fármacos , Sulfonamidas/farmacologia , Humanos , Concentração Inibidora 50 , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).
Assuntos
Descoberta de Drogas , Compostos Heterocíclicos com 2 Anéis/farmacologia , Isoquinolinas/farmacologia , Miotonina Proteína Quinase/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 2 Anéis/química , Humanos , Isoquinolinas/química , Estrutura Molecular , Miotonina Proteína Quinase/metabolismo , Relação Estrutura-AtividadeRESUMO
Replacement of the piperidine ring in the lead benzenesulfonamide Nav1.7 inhibitor 1 with a weakly basic morpholine core resulted in a significant reduction in Nav1.7 inhibitory activity, but the activity was restored by shortening the linkage from methyleneoxy to oxygen. These efforts led to a series of morpholine-based aryl sulfonamides as isoform-selective Nav1.7 inhibitors. This report describes the synthesis and SAR of these analogs.
Assuntos
Morfolinas/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Sulfonamidas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Morfolinas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/químicaRESUMO
Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons.
Assuntos
Descoberta de Drogas , Modelos Biológicos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Neurônios/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Sulfonamidas/farmacologia , Administração Oral , Animais , Dor Crônica/induzido quimicamente , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Adjuvante de Freund , Células HEK293 , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos , Estrutura Molecular , Neurônios/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/químicaRESUMO
Michael addition of thiourea to enones with subsequent intramolecular aminal ether formation provided easy access to furo[2,3-d]thiazinamines and pyrano[2,3-d][1,3]thiazin-2-amines. These amines served as versatile intermediates to a variety of beta-amyloid cleaving enzyme-1 (BACE1) inhibitors.
RESUMO
This Letter describes the synthesis and structure-activity relationships of a series of furo[2,3-d][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine 2e bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3-d]thiazine can serve as a viable bioisostere of the known furo[3,4-d]thiazine.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Furanos/química , Furanos/farmacologia , Tiazinas/química , Tiazinas/farmacologia , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/química , Ácido Aspártico Endopeptidases/metabolismo , Domínio Catalítico , Humanos , Modelos Moleculares , Ligação ProteicaRESUMO
The synthesis, evaluation, and structure-activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Guanidinas/farmacologia , Compostos Macrocíclicos/farmacologia , Prolina/análogos & derivados , Prolina/farmacologia , Inibidores de Proteases/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Peptídeos beta-Amiloides/biossíntese , Animais , Células CACO-2 , Catepsina D/antagonistas & inibidores , Catepsina E/antagonistas & inibidores , Cães , Guanidinas/síntese química , Humanos , Compostos Macrocíclicos/síntese química , Células Madin Darby de Rim Canino , Masculino , Camundongos , Simulação de Acoplamento Molecular , Pepsina A/antagonistas & inibidores , Prolina/síntese química , Inibidores de Proteases/síntese químicaRESUMO
The synthesis, evaluation, and structure-activity relationships of a class of γ-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of γ-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Lactamas/química , Lactamas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Animais , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Lactamas/síntese química , Lactamas/farmacocinética , Camundongos , Modelos Moleculares , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis, evaluation, and structure-activity relationships of a set of related constrained diaminopropane inhibitors of BACE-1 are described. The full in vivo profile of an optimized inhibitor in both normal and P-gp deficient mice is compared with data generated in normal rats.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Diaminas/química , Diaminas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Doença de Alzheimer/tratamento farmacológico , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Cristalografia por Raios X , Diaminas/síntese química , Diaminas/farmacocinética , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Modelos Moleculares , Ratos , Relação Estrutura-AtividadeRESUMO
A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce the bicyclic pyrimidine γ-secretase modulator BMS-932481. The compound showed robust reductions of Aß1-42 and Aß1-40 in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-secretase modulator mechanism, increases in Aß1-37 and Aß1-38 were observed, with no change in the total amount of Aß1-x produced. No Notch-based toxicity was observed, and the overall preclinical profile of BMS-932481 supported its further evaluation in human clinical trials.
RESUMO
By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine- and piperidine-based benzenesulfonamides as potent and selective Nav1.7 inhibitors. However, compound 24, one of the early analogs, failed to reduce phase 2 flinching in the mouse formalin test even at a dose of 100 mpk PO due to insufficient dorsal root ganglion (DRG) exposure attributed to poor membrane permeability. Two analogs with improved membrane permeability showed much increased DRG concentrations at doses of 30 mpk PO, but, confoundingly, only one of these was effective in the formalin test. More data are needed to understand the disconnect between efficacy and exposure relationships.
Assuntos
Analgésicos/química , Analgésicos/uso terapêutico , Dor/tratamento farmacológico , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Descoberta de Drogas , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Dor/metabolismo , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , BenzenossulfonamidasRESUMO
Truncation of the S3 substituent of the biaryl aminothiazine 2, a potent BACE1 inhibitor, led to a low molecular weight aminothiazine 5 with moderate activity. Despite its moderate activity, compound 5 demonstrated significant brain Aß reduction in rodents. The metabolic instability of 5 was overcome by the replacement of the 6-dimethylisoxazole, a metabolic soft spot, with a pyrimidine ring. Thus, truncation of the S3 substituent represents a viable approach to the discovery of orally bioavailable, brain-penetrant BACE1 inhibitors.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Tiazinas/química , Tiazinas/farmacologia , Aminação , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Inibidores Enzimáticos/sangue , Humanos , Camundongos , Simulação de Acoplamento Molecular , Ratos , Relação Estrutura-Atividade , Tiazinas/sangueRESUMO
By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Aß reduction in rat dose-response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease.
RESUMO
A series of Maxi-K openers for the treatment of erectile dysfunction based on the 3-thio-quinolinone core is described. Significant levels of channel opening (up to 550% of control) are seen in transfected oocytes. Functional activity in rabbit corpus cavernosum tissue strips confirms the potential to effect therapy for ED, the effect being maximal for the 3-amino-2-hydroxy thiol side chain.