ABSTRACT
A previous disclosure from this lab highlighted the discovery of pyridyl amides as potent 11ß-HSD1 inhibitors. In order to build additional novelty and polarity into this chemotype, replacement of the hydrogen-bonding carbonyl (CO) pharmacophore with the bioisosteric sulfonyl (SO2) group was examined. Despite initial comparisons suggesting the corresponding sulfonamides exhibited weaker activity versus their carbonyl counterparts, further optimization was performed in an effort to identify various potent and unique leads for the program. Judicious incorporation of polar moieties resulted in the identification of compounds with enhanced potency and lipophilicity profiles, resulting in leads with superior aqueous solubility and liver microsomal stability.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Metabolic Diseases/drug therapy , Sulfonamides/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Binding Sites , Drug Evaluation, Preclinical , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/therapeutic use , Humans , Microsomes, Liver/metabolism , Molecular Docking Simulation , Protein Binding , Protein Structure, Tertiary , Structure-Activity Relationship , Sulfonamides/metabolism , Sulfonamides/therapeutic useABSTRACT
In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.
Subject(s)
Carboxylic Acids/chemistry , Drug Discovery , Factor VIIa/antagonists & inhibitors , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Benzamidines , Crystallography, X-Ray , Dose-Response Relationship, Drug , Factor VIIa/metabolism , Humans , Models, Molecular , Molecular Structure , Serine Proteinase Inhibitors/chemical synthesis , Structure-Activity RelationshipABSTRACT
Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11ß-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Isoquinolines/chemistry , Isoquinolines/pharmacology , Animals , Cell Line , Diabetes Mellitus, Type 2/drug therapy , Enzyme Inhibitors/pharmacokinetics , Humans , Isoquinolines/pharmacokinetics , Mice , Mice, Inbred BALB C , Structure-Activity RelationshipABSTRACT
Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Amides/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Drug Design , Humans , Inhibitory Concentration 50 , Molecular Conformation , Molecular Structure , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
11beta-hydroxysteroid dehydrogenase 1 regulates the tissue availability of cortisol by interconverting cortisone and cortisol. It is capable of functioning as both a reductase and a dehydrogenase depending upon the surrounding milieu. In this work, we have studied the reaction mechanism of a soluble form of human 11beta-hydroxysteroid dehydrogenase 1 and its mode of inhibition by potent and selective inhibitors belonging to three different structural classes. We found that catalysis follows an ordered addition with NADP(H) binding preceding the binding of the steroid. While all three inhibitors tested bound to the steroid binding pocket, they differed in their interactions with the cofactor NADP(H). Compound A, a pyridyl amide bound more efficiently to the NADPH-bound form of 11beta-hydroxysteroid dehydrogenase 1. Compound B, an adamantyl triazole, was unaffected by NADP(H) binding and the sulfonamide, Compound C, showed preferential binding to the NADP+ -bound form of 11beta-hydroxysteroid dehydrogenase 1. These differences were found to augment significant selectivity towards inhibition of the reductase reaction versus the dehydrogenase reaction. This selectivity may translate to differences in the in vivo effects of 11beta-hydroxysteroid dehydrogenase 1 inhibitors.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenases/metabolism , Pyridines/pharmacology , Sulfonamides/pharmacology , Triazoles/pharmacology , Humans , Kinetics , NADP/metabolismABSTRACT
There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.
Subject(s)
Amides/chemical synthesis , Aminopyridines/chemical synthesis , Anticoagulants/chemical synthesis , Factor Xa Inhibitors , Thiophenes/chemical synthesis , ortho-Aminobenzoates/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Crystallography, X-Ray , Dogs , Humans , In Vitro Techniques , Male , Models, Molecular , Prothrombin Time , Rats , Rats, Wistar , Structure-Activity Relationship , Thiophenes/pharmacokinetics , Thiophenes/pharmacology , Venous Thrombosis/drug therapy , ortho-Aminobenzoates/pharmacokinetics , ortho-Aminobenzoates/pharmacologyABSTRACT
Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability.
Subject(s)
Cation Transport Proteins/antagonists & inhibitors , Guanidines/administration & dosage , Imidazoles/administration & dosage , Membrane Proteins/antagonists & inhibitors , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Administration, Oral , Biological Availability , Cation Transport Proteins/metabolism , Cell Line , Guanidines/chemistry , Guanidines/pharmacokinetics , Humans , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Membrane Proteins/metabolism , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Sodium-Hydrogen Exchanger 1 , Sodium-Hydrogen Exchangers/metabolism , StereoisomerismABSTRACT
Compound 1 was identified by high throughput screening as a novel, potent, non-amidine factor Xa inhibitor with good selectivity against thrombin and trypsin. A series of modifications of the three aromatic groups of 1 was investigated. Substitution of chlorine or bromine for fluorine on the aniline ring led to the discovery of subnanomolar factor Xa inhibitors. Positions on the anthranilic acid ring that can accommodate further substitution were also identified.
Subject(s)
Factor Xa Inhibitors , Thiophenes/pharmacology , ortho-Aminobenzoates/pharmacology , Animals , Anticoagulants/chemical synthesis , Anticoagulants/pharmacology , Cattle , Heterocyclic Compounds/pharmacology , Humans , Indicators and Reagents , Kinetics , Prothrombin Time , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Thiophenes/chemistry , Thrombin/antagonists & inhibitors , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/pharmacology , ortho-Aminobenzoates/chemistryABSTRACT
A novel series of triaryloxypyridines have been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. Inhibitor 5e has a K(I) against factor Xa of 0.12nM and is greater than 8000- and 2000-fold selective over two related serine proteases, thrombin and trypsin, respectively. The 4-position of the central pyridine has been identified as a site that tolerates various substitutions without deleterious effects on potency and selectivity. This suggests that the 4-position of the pyridine ring is an ideal site for chemical modifications to identify inhibitors with improved pharmacokinetic characteristics. This investigation has resulted in inhibitor 5d, which has an oral availability of 6% in dogs. The synthesis, in vitro activity, and in vivo profile of this class of inhibitors is outlined.