RESUMO
A global biopharma company, GSK, and the University of Strathclyde have developed an expansive and transformative research and training partnership originating in chemistry-aligned disciplines, with subsequent extensive expansion across further areas of the company. This has opened unique approaches for the delivery of collaborative research innovations while also enhancing the professional development and learning of GSK personnel, in addition to other embedded researchers and collaborating scientists, on a pathway towards more rapid and efficient discovery of new medicines.
RESUMO
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Inibidores do Fator Xa , Pirrolidinonas/química , Inibidores de Serina Proteinase/química , Animais , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Masculino , Modelos Moleculares , Pirrolidinonas/farmacocinética , Pirrolidinonas/farmacologia , Ratos , Ratos Sprague-Dawley , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities.
Assuntos
Inibidores do Fator Xa , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Animais , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Desenho de Fármacos , Masculino , Modelos Moleculares , Pirrolidinonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaRESUMO
Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.
Assuntos
Anticoagulantes/síntese química , Inibidores do Fator Xa , Fator Xa/química , Morfolinas/síntese química , Pirrolidinas/síntese química , Sulfonamidas/síntese química , Animais , Anticoagulantes/química , Anticoagulantes/farmacologia , Cristalografia por Raios X , Cães , Feminino , Humanos , Ligantes , Masculino , Modelos Moleculares , Estrutura Molecular , Morfolinas/química , Morfolinas/farmacologia , Ligação Proteica , Tempo de Protrombina , Pirrolidinas/química , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Albumina Sérica/química , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
The rate of reduction of nitrite by trimethylamine-borane was followed by observing the decrease in nitrite absorbance under pseudo-first-order conditions. The reaction is acid-catalyzed and exhibits a first-order dependence on both amine-borane and total nitrite concentration. The molar equivalence of NaNO(2) to (CH(3))(3)NBH(3) = 2:1. Equimolar amounts of hydrogen and nitrous oxide are formed, and the molar ratio of nitrite reacted to N(2)O produced is 2:1. In concentrated HCl or H(2)SO(4), a correlation of rate with the Hammett acidity function, h(o), is observed. The reaction is subject to a pronounced inversesolvent isotope effect (k(D)()2(O)/k(H)()2(O) approximately 2.7) and a modest normal substrate effect (k((CH)()3())()3(N.BH)()3/k((CH)()3())()3(N.BD)()3 approximately 1.4). The reaction is first-order in H(3)O(+) in the region pH 0.7-2.7, but a second-order dependence is observed above pH 4 with the transition occurring at pH approximately pK(a) for HNO(2). Results are consistent with a mechanistic model involving preequilibration protonation of molecular nitrous acid followed by rate-limiting hydride attack on H(2)ONO(+) or free NO(+) to produce nitrosyl hydride as a reactive intermediate.
RESUMO
In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and ≥tenfold, respectively.
Assuntos
Química Farmacêutica/educação , Desenho de Fármacos , Descoberta de Drogas/métodos , Currículo , Indústria Farmacêutica/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Inibidores de Fosfoinositídeo-3 Quinase , SolubilidadeRESUMO
The synthetic entry to new classes of dual fXa/thrombin and selective thrombin inhibitors with significant oral bioavailability is described. This was achieved through minor modifications to the sulfonamide group in our potent and selective fXa inhibitor (E)-2-(5-chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide and these observed activity changes have been rationalised using structural studies.
Assuntos
Inibidores do Fator Xa , Fibrinolíticos/farmacologia , Morfolinas/farmacologia , Sulfonamidas/farmacologia , Trombina/antagonistas & inibidores , Animais , Cães , Fibrinolíticos/síntese química , Fibrinolíticos/química , Modelos Moleculares , Estrutura Molecular , Morfolinas/síntese química , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.
Assuntos
Antitrombina III/farmacologia , Fibrinolíticos/farmacologia , Pirrolidinonas/farmacologia , Trombina/efeitos dos fármacos , Administração Oral , Animais , Antitrombina III/síntese química , Disponibilidade Biológica , Fibrinolíticos/síntese química , Masculino , Pirrolidinonas/síntese química , Ratos , Ratos WistarRESUMO
Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.