RESUMO
The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Imediatamente Precoces/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Desenho de Fármacos , Glucocorticoides/química , Ácido Glucurônico/química , Proteínas Imediatamente Precoces/química , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Inibidores de Proteínas Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Ratos , Relação Estrutura-AtividadeRESUMO
Ortho-substituted biphenyl moieties are widely used in drug design. We herein report a successful use of the perpendicular conformation of the alpha-substituted phenylcyclopropyl groups to mimic the aplanar, biologically active conformation of the ortho-substituted biphenyl moieties to achieve structural diversity. This is exemplified by the design and synthesis of a series of highly potent pyrazole bicyclic-based Factor Xa (FXa) inhibitors bearing alpha-substituted phenylcyclopropyl P4 moieties. The designed perpendicular conformation was confirmed by the X-ray structure of FXa-bound compound 2r. The potential structural basis for the high FXa potency in the phenylcyclopropyl P4 analogs and their improved FXa inhibitory activities compared with the biphenyl P4 counterparts are discussed.
Assuntos
Compostos de Bifenilo/química , Ciclopropanos/química , Inibidores do Fator Xa , Fator Xa/química , Sítios de Ligação , Coagulação Sanguínea/efeitos dos fármacos , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Desenho de Fármacos , Elétrons , Humanos , Cinética , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Trombose/tratamento farmacológicoRESUMO
Serum and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine protein kinase of the AGC family which participates in the control of epithelial ion transport and is implicated in proliferation and apoptosis. We report here the 1.9 A crystal structure of the catalytic domain of inactive human SGK1 in complex with AMP-PNP. SGK1 exists as a dimer formed by two intermolecular disulfide bonds between Cys258 in the activation loop and Cys193. Although most of the SGK1 structure closely resembles the common protein kinase fold, the structure around the active site is unique when compared to most protein kinases. The alphaC helix is not present in this inactive form of SGK1 crystal structure; instead, the segment corresponding to the C helix forms a beta-strand that is stabilized by the N-terminal segment of the activation loop through a short antiparallel beta-sheet. Since the differences from other kinases occur around the ATP binding site, this structure can provide valuable insight into the design of selective and highly potent ATP-competitive inhibitors of SGK1 kinase.
Assuntos
Adenilil Imidodifosfato/química , Proteínas Imediatamente Precoces/química , Proteínas Serina-Treonina Quinases/química , Trifosfato de Adenosina/metabolismo , Adenilil Imidodifosfato/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Dimerização , Humanos , Interações Hidrofóbicas e Hidrofílicas , Proteínas Imediatamente Precoces/isolamento & purificação , Proteínas Imediatamente Precoces/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Conformação Proteica , Proteínas Serina-Treonina Quinases/isolamento & purificação , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Alinhamento de SequênciaRESUMO
As part of an ongoing effort to prepare orally active factor Xa inhibitors using structure-based drug design techniques and molecular recognition principles, a systematic study has been performed on the pharmacokinetic profile resulting from replacing the benzamidine in the P1 position with less basic benzamidine mimics or neutral residues. It is demonstrated that lowering the pK(a) of the P1 ligand resulted in compounds (3-benzylamine, 15a; 1-aminoisoquinoline, 24a; 3-aminobenzisoxazole, 23a; 3-phenylcarboxamide, 22b; and 4-methoxyphenyl, 22a) with improved pharmacokinetic features mainly as a result of decreased clearance, increased volume of distribution, and enhanced oral absorption. This work resulted in a series of potent and orally bioavailable factor Xa inhibitors that ultimately led to the discovery of SQ311, 24a. SQ311, which utilizes a 1-aminoisoquinoline as the P1 ligand, inhibits factor Xa with a K(i) of 0.33 nM and demonstrates both good in vivo antithrombotic efficacy and oral bioavailability.
Assuntos
Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Benzamidinas/farmacologia , Inibidores do Fator Xa , Guanidinas/farmacologia , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Anticoagulantes/farmacocinética , Sítios de Ligação/efeitos dos fármacos , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Desenho de Fármacos , Ligação de Hidrogênio , Indicadores e Reagentes , Absorção Intestinal , Mimetismo Molecular , Coelhos , Relação Estrutura-Atividade , Trombina/químicaRESUMO
The identification of indeno[1,2-c]pyrazol-4-ones as inhibitors of cyclin-dependent kinases (CDKs) has led to the discovery of a series of novel and potent compounds. Herein, we report the effects of substitutions at C3 of the indeno[1,2-c]pyrazol-4-one core with alkyls, heterocycles, and substituted phenyls. Substitutions at the para position of the phenyl ring at C3 were generally well-tolerated; however, larger groups were generally inactive. For alkyls directly attached to C3, longer chain substituents were not tolerated; however, shorter alkyl groups and cyclic alkyls were acceptable. In general, the heterocycles at C3 gave the most potent analogues. One such heterocycle, 24j, was examined in detail and was determined to have a biological profile consistent with CDK inhibition. An X-ray crystal structure of one of the alkyl compounds, 13q, complexed with CDK2 was determined and showed the inhibitor residing in the adenosine 5'-triphosphate pocket of the enzyme.
Assuntos
Quinases relacionadas a CDC2 e CDC28 , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Proteínas Proto-Oncogênicas , Pirazóis/síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose , Divisão Celular/efeitos dos fármacos , Cristalografia por Raios X , Quinase 2 Dependente de Ciclina , Quinase 4 Dependente de Ciclina , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Cinética , Modelos Moleculares , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/química , Pirazóis/farmacologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
New indeno[1,2-c]pyrazol-4-one cyclin dependent kinase inhibitors have been disclosed. The most promising compounds are nanomolar enzyme inhibitors with excellent activity against tumor cells. The most advanced compound retains cell culture activity even in the presence of human serum proteins. The most advanced compound did not kill the normal fibroblast line AG1523.