RESUMO
Optimization of a lead thiazole amide MF-152 led to the identification of potent bicyclic heteroaryl SCD1 inhibitors with good mouse pharmacokinetic profiles. In a view to target the liver for efficacy and to avoid SCD1 inhibition in the skin and eyes where adverse effects were previously observed in rodents, representative systemically-distributed SCD1 inhibitors were converted into liver-targeting SCD1 inhibitors.
Assuntos
Desenho de Fármacos , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Tiazóis/síntese química , Tiazóis/farmacologia , Amidas , Animais , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/toxicidade , Fígado/efeitos dos fármacos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piperazinas/farmacocinética , Piperazinas/toxicidade , Ratos , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/toxicidadeRESUMO
Our series of competitive antagonists against the G-protein coupled receptor P2Y(14) were found to be highly shifted in the presence of serum (>99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323-fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared (7a-7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile.
Assuntos
Pró-Fármacos/química , Antagonistas do Receptor Purinérgico P2/química , Receptores Purinérgicos P2/química , Disponibilidade Biológica , Humanos , Microssomos Hepáticos/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Ligação Proteica , Antagonistas do Receptor Purinérgico P2/síntese química , Antagonistas do Receptor Purinérgico P2/farmacocinética , Receptores Purinérgicos P2/metabolismo , Relação Estrutura-AtividadeRESUMO
A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY(14) with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y(14) with a good pharmacokinetic profile.
Assuntos
Ácidos Carboxílicos/síntese química , Naftalenos/síntese química , Antagonistas do Receptor Purinérgico P2/síntese química , Receptores Purinérgicos P2 , Difosfato de Uridina , Animais , Ligação Competitiva , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/farmacologia , Camundongos , Estrutura Molecular , Naftalenos/química , Naftalenos/farmacocinética , Naftalenos/farmacologia , Pan troglodytes , Ligação Proteica/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2/química , Antagonistas do Receptor Purinérgico P2/farmacocinética , Antagonistas do Receptor Purinérgico P2/farmacologia , Receptores Purinérgicos P2Y , Relação Estrutura-AtividadeRESUMO
While several efficient processes exist to effect the stereoselective creation of carbon-carbon bonds in the α- and ß-position of carbonyls, functionalization of the γ-position is much more challenging. We disclose an alternative methodology exploiting the Cu-promoted S(N)2' reaction to achieve the addition of various nucleophiles upon the allylic lactones 5a-d which lead to the generation of the desired γ-functionalized α,ß-unsaturated aldehydes 6 following in situ hydrolysis.
Assuntos
Carbono/química , Cobre/química , Lactonas/síntese química , Aldeídos/química , Alquilação , Catálise , Hidrólise , Estrutura Molecular , EstereoisomerismoRESUMO
Potent and orally bioavailable SCD inhibitors built on an azetidinyl pyridazine scaffold were identified. In a one-month gDIO mouse model of obesity, we demonstrated that there was no therapeutic index even at low doses; efficacy in preventing weight gain tracked closely with skin and eye adverse events. This was attributed to the local SCD inhibition in these tissues as a consequence of the broad tissue distribution observed in mice for this class of compounds. The search for new structural scaffolds which may display a different tissue distribution was initiated. In preparation for an HTS campaign, a radiolabeled azetidinyl pyridazine displaying low non-specific binding in the scintillation proximity assay was prepared.
Assuntos
Azetidinas/química , Inibidores Enzimáticos/química , Piridazinas/química , Estearoil-CoA Dessaturase/antagonistas & inibidores , Animais , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Camundongos , Ligação Proteica , Piridazinas/síntese química , Piridazinas/farmacologia , Estearoil-CoA Dessaturase/metabolismoRESUMO
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
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
We have characterized the structures of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E(2) synthase-1 (mPGES-1) in intact cells using bifunctional and photo-activatable crosslinking agents. A dimeric complex was detected for COX-2 by both crosslinking approaches, consistent with the crystal structure of the enzyme. For mPGES-1, treatment of A549 cells with disuccinimidyl suberate yielded immunoreactive protein bands corresponding to a dimer (33 kDa) and a trimer (45 kDa), as observed for the isolated enzyme. Photo-crosslinking with photoactivatable methionine in intact cells generated complexes with molecular weights corresponding to the dimer (33 kDa) and two putative trimer forms (50 and 55 kDa). Treatment with the selective mPGES-1 inhibitor MF63 prevented the formation of the 50 and 55 kDa crosslinked complexes, while an inactive structural analogue had no effect. Our data indicate that COX-2 forms a dimer in intact cells and that mPGES-1 has an oligomeric structure that can be disrupted by a selective inhibitor.
Assuntos
Ciclo-Oxigenase 2/química , Oxirredutases Intramoleculares/química , Western Blotting , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Dimerização , Dinoprostona/biossíntese , Eletroforese em Gel de Poliacrilamida , Inibidores Enzimáticos/farmacologia , Humanos , Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/metabolismo , Fotoquímica , Prostaglandina-E Sintases , Conformação Proteica , Raios UltravioletaRESUMO
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
Highly potent, selective, and bioavailable inhibitors of human, mouse, or rat cathepsin S are described. The key structural features combine a sulfonyl moiety attached to a large group in P2 and a small substituent in P3.
Assuntos
Catepsinas/antagonistas & inibidores , Química Farmacêutica/métodos , Animais , Inibidores de Cisteína Proteinase/química , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
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
[reaction: see text] The first synthesis of (-)-panacene has been accomplished in concise, highly stereoselective fashion from commercially available 2-methoxy-6-methylbenzoic acid (15 steps, 8.3% overall yield). The synthesis unambiguously establishes the correct relative and absolute configuration of panacene, and demonstrates the serviceability of Pd(II)-mediated tandem intramolecular alkoxycarbonylation-lactonization for the expedient assembly of its tricyclic core, and the dual role of asymmetric alkynylation as an initial source of chirality and as a powerful tool for manipulating diastereoselectivity.
Assuntos
Alcadienos/química , Alcadienos/síntese química , Hidrocarbonetos Bromados/síntese química , Animais , Aplysia/química , Catálise , Hidrocarbonetos Bromados/química , Estrutura Molecular , Paládio/química , EstereoisomerismoRESUMO
The synthesis and biological profile of a novel series of potent and selective inhibitors of cysteine protease cathepsin K (Cat K) are described. Pharmacokinetic evaluation of 12 indicated that some members of this series could be suitable candidates to develop new orally active therapeutic agents for the treatment of osteoporosis.
Assuntos
Catepsinas/antagonistas & inibidores , Nitrilas/química , Osteoporose/tratamento farmacológico , Área Sob a Curva , Catepsina B/química , Catepsina K , Catepsina L , Catepsinas/química , Química Farmacêutica , Cisteína Endopeptidases/química , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos MolecularesRESUMO
[reaction: see text] The challenging structural features and important biological activity of (+)-compactin (1) explain the substantial synthetic interest that it has generated. We report a novel enantioselective approach to the advanced intermediate 2a, which constitutes a formal synthesis of (+)-1. The sequence utilizes MacMillan's organocatalytic Mukaiyama-Michael reaction, which stereoselectively adds the silyloxyfuran 6 to alpha,beta-unsaturated aldehyde 7. The chirality generated in this reaction guides the formation of the other three consecutive stereocenters found in 2a.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Lovastatina/análogos & derivados , Ciclização , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Lovastatina/síntese química , Lovastatina/química , Estrutura Molecular , EstereoisomerismoRESUMO
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
The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The non-basic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compounds are 10- to 20-fold more potent than the corresponding amide derivatives. Compound 8 is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins.
Assuntos
Catepsinas/antagonistas & inibidores , Etilaminas/farmacologia , Inibidores de Proteases/síntese química , Amidas/química , Catepsina K , Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Etilaminas/síntese química , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
Prior reports from our laboratories have identified the nonpeptidic inhibitor 2 as a potent and selective Cathepsin K (Cat K) inhibitor. Modelling studies suggested that the introduction of a NH linker between the P3 aryl and P2 leucinamide moieties would allow the formation of a H-bond with the Gly66 residue of Cat K, hopefully increasing potency. Aniline 4 was thus synthesized and showed improved potency over its predecessor 2. Further modelling concluded that a 2-substituted five membered ring could more adequately place the P3 moiety of 4 into the S3 pocket of Cat K. The synthesis of the 2-substituted thiophene 5 confirmed this hypothesis by displaying a slight increase in potency against Cat K (>10-fold increase in potency vs 2) and a good selectivity profile against Cathepsins B, L, and S. This rationally designed inhibitor 5 also displayed increased potency in a functional bone resorption assay (10nM) versus 2 (95 nM).
Assuntos
Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/química , Sítios de Ligação , Catepsina K , Inibidores de Cisteína Proteinase/farmacologia , Ligação de Hidrogênio , Modelos MolecularesRESUMO
A novel series of nonpeptidic biaryl compounds was identified as potent and reversible inhibitors of cathepsin K. The P2-P3 amide bond of a known amino acetonitrile dipeptide 1 was replaced with a phenyl ring, thereby giving rise to this biaryl series that retained potency vs cathepsin K and showed an improved selectivity profile against other cathepsins. Structural modification within this series resulted in the identification of compound (R)-2, a potent human cathepsin K inhibitor (IC(50) = 3 nM) that is selective versus cathepsins B (IC(50) = 3950 nM), L (IC(50) = 3725 nM), and S (IC(50) = 2010 nM). In an in vitro assay involving rabbit osteoclasts and bovine bone, compound (R)-2 inhibited bone resorption with an IC(50) of 95 nM. It was shown that, unlike some peptidic nitrile inhibitors of cysteine proteases, the nitrile moiety of (R)-2 is not converted to the corresponding amide 3 by cathepsin K. This indicates that this class of nonpeptidic nitrile inhibitors is unlikely to be hydrolyzed by cysteine proteases. Furthermore, the inhibition of cathepsin K by compound (R)-2 was shown to be fully reversible and not observably time-dependent. To demonstrate the efficacy of compound (R)-2 in vivo, it was administered to ovariectomized (OVX) rhesus monkeys at 20 mg/kg, po once daily for 8 days, and a urinary marker of bone turnover, N-telopeptide of type I collagen (uNTx), was measured. During the eight-day dosing period, the mean reduction by compound (R)-2 in uNTx was 80% (p < 0.001). This demonstrates that inhibition of cathepsin K leads to an inhibition of this bone resorption marker in OVX rhesus monkeys and strongly suggests that inhibition of cathepsin K is a viable therapeutic approach for the treatment of osteoporosis.
Assuntos
Compostos de Bifenilo/síntese química , Catepsinas/antagonistas & inibidores , Nitrilas/síntese química , Piperazinas/síntese química , Inibidores de Proteases/síntese química , Animais , Biomarcadores/urina , Compostos de Bifenilo/farmacocinética , Compostos de Bifenilo/farmacologia , Reabsorção Óssea/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Catepsina B/antagonistas & inibidores , Catepsina B/química , Catepsina K , Catepsina L , Catepsinas/química , Bovinos , Colágeno/urina , Colágeno Tipo I , Cisteína Endopeptidases , Humanos , Técnicas In Vitro , Macaca mulatta , Nitrilas/química , Nitrilas/farmacocinética , Nitrilas/farmacologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Ovariectomia , Peptídeos/urina , Piperazinas/farmacocinética , Piperazinas/farmacologia , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Coelhos , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
A large-scale, chromatography-free synthesis of a potent and selective Cathepsin K inhibitor 1 is reported. The key asymmetric center was installed by addition of (R)-pantolactone to the in situ-generated ketene 4a. The final step of the convergent synthesis of 1 was completed via Suzuki coupling of aryl bromide 7a with unprotected aryl piperazine boronic acid 13. Residual palladium and iron generated in the Suzuki coupling were efficiently removed from crude 1 via a simple extractive workup using lactic acid.