RESUMO
The voltage gated sodium channel Nav1.7 represents an interesting target for the treatment of pain. Human genetic studies have identified the crucial role of Nav1.7 in pain signaling. Herein, we report the design and synthesis of a novel series of benzenesulfonamide-based Nav1.7 inhibitors. Structural-activity relationship (SAR) studies were undertaken towards improving Nav1.7 activity and minimizing CYP inhibition. These efforts resulted in the identification of compound 12k, a highly potent Nav1.7 inhibitor with a thousand-fold selectivity over Nav1.5 and negligible CYP inhibition.
Assuntos
Citocromo P-450 CYP3A/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/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 , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , 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/química , BenzenossulfonamidasRESUMO
BACKGROUND: Selective and reversible inhibitors of human Cathepsin K (CatK), including odanacatib (ODN), have been developed as potential therapeutics for the treatment of osteoporosis. Inhibitors of human CatK show significantly less potency for the rodent enzymes compared with that for the human or rabbit enzymes; thus the Schenk model in growing rabbit was developed as a screening assay for the in vivo activity of CatK inhibitors in blocking bone resorption. METHODS: In this study, the efficacy of the selective inhibitors L-833905, L-006235, L-873724, and L-1037536 (ODN) of human CatK in the rapidly growing rabbit 'Schenk' model (age seven weeks) was compared to vehicle, using the bisphosphonate, alendronate (ALN), as a positive control, to assess inhibition of bone resorption. An enzyme inhibition assay (EIA) and an in vitro bone resorption assay using rabbit osteoclasts on bovine cortical bone slices were performed to evaluate the potency of these CatK inhibitors. Bone mineral density of the distal femur (DFBMD) was measured after ten days of treatment using ex vivo DXA densitometry. RESULTS: Results of the EIA using rabbit CatK and the rabbit bone resorption assay showed that three of the four compounds (L-006235, L-873724, and ODN) had similar potencies in the reduction of collagen degradation. L-833905 appeared to be a weaker inhibitor of CatK. Taking into account the respective in vitro potencies and pharmacokinetic profiles via oral administration, the efficacy of these four CatK inhibitors was demonstrated in a dose-related manner in the growing rabbit. Significant increases in DFBMD in animals dosed with the CatK inhibitors compared to vehicle were seen. CONCLUSIONS: Efficacy of the CatK inhibitors in the Schenk rabbit correlated well with that in the in vitro rabbit bone resorption assay and in the ovariectomized rabbit model as previously published. Hence, these studies validated the rabbit Schenk assay as a rapid and reliable in vivo model for prioritizing human CatK inhibitors as potential therapeutic agents.
Assuntos
Conservadores da Densidade Óssea/farmacologia , Densidade Óssea/efeitos dos fármacos , Catepsina K/efeitos dos fármacos , Animais , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Feminino , Fêmur/efeitos dos fármacos , Humanos , Modelos Animais , Nitrilas/farmacologia , Piperazinas/farmacologia , Coelhos , Distribuição Aleatória , Tiazóis/farmacologiaRESUMO
Elevated levels of stearoyl-CoA desaturase (SCD) activity have been implicated in metabolic disorders such as obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed inhibitors, our research efforts have been focused on the search for new liver-targeting compounds. This work has led to the discovery of novel, potent and liver-selective acyclic linker SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Fígado/enzimologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Acetatos/farmacologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Hidrólise , Concentração Inibidora 50 , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Químicos , Obesidade/tratamento farmacológico , Estearoil-CoA Dessaturase/química , Relação Estrutura-Atividade , Tetrazóis/farmacologiaRESUMO
Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.
Assuntos
Inibidores Enzimáticos/farmacologia , Fígado/efeitos dos fármacos , Pirrolidinas/farmacologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células Hep G2 , Humanos , Fígado/enzimologia , Fígado/metabolismo , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Estearoil-CoA Dessaturase/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An in vitro screening protocol was used to transform a systemically-distributed SCD inhibitor into a liver-targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP transporters, as demonstrated by uptake studies in transfected cell lines, and likely serves as a critical component of the observed liver-targeted tissue distribution profile. Preclinical anti-diabetic oGTT efficacy is demonstrated with nicotinic acid-based, liver-targeting SCD inhibitor 10, and studies with a close-structural analog devoid of SCD1 activity, suggest this efficacy is a result of on-target activity.
Assuntos
Inibidores Enzimáticos/química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Ácidos Nicotínicos/química , Estearoil-CoA Dessaturase/antagonistas & inibidores , Administração Oral , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Ácidos Nicotínicos/síntese química , Ácidos Nicotínicos/farmacocinética , Ácidos Nicotínicos/farmacologia , Ratos , Estearoil-CoA Dessaturase/metabolismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
MK-0674 is a potent and selective cathepsin K inhibitor from the same structural class as odanacatib with a comparable inhibitory potency profile against Cat K. It is orally bioavailable and exhibits long half-life in pre-clinical species. In vivo studies using deuterated MK-0674 show stereoselective epimerization of the alcohol stereocenter via an oxidation/reduction cycle. From in vitro incubations, two metabolites could be identified: the hydroxyleucine and the glucuronide conjugate which were confirmed using authentic synthetic standards.
Assuntos
Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/farmacocinética , Catepsina K/antagonistas & inibidores , Inibidores de Cisteína Proteinase/administração & dosagem , Inibidores de Cisteína Proteinase/farmacocinética , Descoberta de Drogas/métodos , Administração Oral , Animais , Disponibilidade Biológica , Compostos de Bifenilo/química , Catepsina K/metabolismo , Inibidores de Cisteína Proteinase/química , Cães , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Macaca mulatta , Coelhos , RatosRESUMO
Amino ketone warheads were explored as alternatives to the nitrile group of a potent and selective cathepsin K inhibitor. The resulting compounds were potent and selective inhibitors of cathepsin K and these nitrile replacements had a significant effect on metabolism and pharmacokinetics.
Assuntos
Compostos de Bifenilo/síntese química , Catepsina K/antagonistas & inibidores , Catepsina K/química , Química Farmacêutica/métodos , Cetonas/química , Nitrilas/química , Animais , Bile/metabolismo , Compostos de Bifenilo/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cetonas/análise , Modelos Químicos , Osteoporose/tratamento farmacológico , Ratos , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.
Assuntos
Compostos de Bifenilo/farmacologia , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacologia , Animais , Azepinas/química , Azepinas/farmacologia , Catepsina K , Colágeno/efeitos dos fármacos , Colágeno/imunologia , Cães , Fibroblastos/efeitos dos fármacos , Humanos , Modelos Biológicos , Estrutura Molecular , Osteoporose Pós-Menopausa/tratamento farmacológico , Pele/citologia , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologiaRESUMO
A new series of nonpeptidic cathepsin K inhibitors that are based on a beta-substituted cyclohexanecarboxamide motif has been developed. Lead optimization yielded compounds with sub-nanomolar potency and exceptional selectivity profiles against cathepsins B, L, and S. Use of fluorine atoms to block metabolism on the cyclohexyl ring led to compounds with excellent pharmacokinetic properties. Considering the well-established role of cathepsin K in osteoclast-mediated bone turnover, compounds such as (-)-34a (hrab Cat K IC(50) 0.28 nM; >800-fold selectivity vs Cat B, L, and S; PK data in dogs: F 55%, t(1/2) = 15 h) exhibit great potential for development as an orally bioavailable therapeutic for treatment of diseases that involve bone loss.
Assuntos
Amidas/síntese química , Aminoacetonitrila/análogos & derivados , Catepsinas/antagonistas & inibidores , Cicloexanos/síntese química , Amidas/química , Amidas/farmacologia , Aminoacetonitrila/síntese química , Aminoacetonitrila/química , Aminoacetonitrila/farmacologia , Animais , Disponibilidade Biológica , Catepsina K , Catepsinas/química , Cristalografia por Raios X , Cicloexanos/química , Cicloexanos/farmacologia , Cães , Meia-Vida , Masculino , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors of the human sodium channel hNaV1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNaV1.7 while minimizing off-target safety concerns and generated compound 3. This agent displayed significant analgesic effects in rodent models of acute and inflammatory pain and demonstrated that binding to the voltage sensor domain 4 site of NaV1.7 leads to an analgesic effect in vivo. Our findings corroborate the importance of hNaV1.7 as a drug target for the treatment of pain.
RESUMO
As an exceptionally potent antimitotic macrolide, altohyrtin A/spongistatin 1 shows great promise in cancer chemotherapy but its extreme scarcity in the natural sponges has halted its further preclinical development. A highly stereocontrolled total synthesis, which exploits boron-mediated aldol bond constructions, has been realized to provide, for the first time, a useful amount of synthetic material.
RESUMO
The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.
Assuntos
Acetatos/síntese química , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Fígado/enzimologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Tetrazóis/síntese química , Acetatos/química , Acetatos/farmacologia , Animais , Linhagem Celular , Difusão , Cães , Feminino , Glândula de Harder/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Técnicas In Vitro , Transportador 1 de Ânion Orgânico Específico do Fígado , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ratos , Ratos Sprague-Dawley , Pele/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Especificidade da Espécie , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacologia , Distribuição TecidualRESUMO
Herein, we report on the identification of nonbasic, potent, and highly selective, nitrile-containing cathepsin K (Cat K) inhibitors that are built on our previously identified cyclohexanecarboxamide core structure. Subsequent to our initial investigations, we have found that incorporation of five-membered heterocycles as P2-P3 linkers allowed for the introduction of a methyl sulfone P3-substitutent that was not tolerated in inhibitors containing a six-membered aromatic P2-P3 linker. The combination of a five-membered N-methylpyrazole linker and a methyl sulfone in P3 yielded subnanomolar Cat K inhibitors that were minimally shifted (<10-fold) in our functional bone resorption assay. Issues that arose because of metabolic demethylation of the N-methylpyrazole were addressed through introduction of a 2,2,2-trifluoroethyl substituent. This culminated in the identification of 31 (MK-1256), a potent (Cat K IC 50 = 0.62 nM) and selective (>1100-fold selectivity vs Cat B, L, S, C, H, Z, and V, 110-fold vs Cat F) inhibitor of cathepsin K that is efficacious in a monkey model of osteoporosis.
Assuntos
Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/uso terapêutico , Nitrilas/química , Osteoporose/tratamento farmacológico , Osteoporose/enzimologia , Pirazóis/química , Pirazóis/uso terapêutico , Sulfonas/química , Sulfonas/uso terapêutico , Animais , Catepsina K , Catepsinas/metabolismo , Inibidores de Cisteína Proteinase/metabolismo , Inibidores de Cisteína Proteinase/farmacocinética , Modelos Animais de Doenças , Cães , Feminino , Cinética , Macaca mulatta , Modelos Moleculares , Estrutura Molecular , Pirazóis/metabolismo , Pirazóis/farmacocinética , Ratos , Relação Estrutura-Atividade , Sulfonas/metabolismo , Sulfonas/farmacocinéticaRESUMO
Nitrile-based inhibitors of cathepsin K have been known for some time and mechanism-of-action studies have demonstrated that cysteinyl proteases interact with nitriles in a reversible fashion. Three main classes of nitrile-containing inhibitors have been published in the cathepsin K field: (i) cyanamides, (ii) aromatic nitriles, and (iii) aminoacetonitriles. A computational approach was used to calculate the theoretical reactivities of diverse nitriles and this was found to correlate with their extent of reactivity with free cysteine. Moreover, there is a tentative link between high reactivity with cysteine and the potential to lead to irreversible covalent binding to proteins.
Assuntos
Inibidores de Cisteína Proteinase/síntese química , Nitrilas/química , Catepsina K , Catepsinas/antagonistas & inibidores , Biologia Computacional , Cisteína/química , Inibidores de Cisteína Proteinase/farmacologia , Eletroquímica , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , NADP/química , OxirreduçãoRESUMO
Further SAR study around the central 1,2-disubstituted phenyl of the previously disclosed Cat K inhibitor (-)-1 has demonstrated that the solvent exposed P2-P3 linker can be replaced by various 5- or 6-membered heteroaromatic rings. While some potency loss was observed in the 6-membered heteroaromatic series (IC(50)=1 nM for pyridine-linked 4 vs 0.5 nM for phenyl-linked (+/-)-1), several inhibitors showed a significantly decreased shift in the bone resorption functional assay (10-fold for pyridine 4 vs 53-fold for (-)-1). Though this shift was not reduced in the 5-membered heteroaromatic series, potency against Cat K was significantly improved for thiazole 9 (IC(50)=0.2 nM) as was the pharmacokinetic profile of N-methyl pyrazole 10 over our lead compound (-)-1.
Assuntos
Amidas/química , Amidas/farmacologia , Catepsinas/antagonistas & inibidores , Cicloexanos/química , Cicloexanos/farmacologia , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Amidas/síntese química , Animais , Catepsina K , Cicloexanos/síntese química , Inibidores de Cisteína Proteinase/síntese química , Humanos , Hidrocarbonetos Aromáticos/química , Concentração Inibidora 50 , Estrutura Molecular , Coelhos , Relação Estrutura-AtividadeRESUMO
The convergent synthesis of the C1-C15 AB-spiroacetal subunit of altohyrtin A/spongistatin 1 is described. This highly stereocontrolled synthesis relies on matched boron aldol reactions of chiral methyl ketones, under Ipc(2)BCl mediation, to establish the C5, C9 and C11 stereocentres, and formation of the desired thermodynamic spiroacetal under acidic conditions. The scalable synthetic sequence developed provided access to multi-gram quantities of , thus enabling the successful completion of the total synthesis of altohyrtin A/spongistatin 1, as reported in Part 4.