ABSTRACT
A multidisciplinary, fragment-based screening approach involving protein ensemble docking and biochemical and NMR assays is described. This approach led to the discovery of several structurally diverse, neutral surrogates for cationic factor VIIa P1 groups, which are generally associated with poor pharmacokinetic (PK) properties. Among the novel factor VIIa inhibitory fragments identified were aryl halides, lactams, and heterocycles. Crystallographic structures for several bound fragments were obtained, leading to the successful design of a potent factor VIIa inhibitor with a neutral lactam P1 and improved permeability.
Subject(s)
Drug Design , Factor VIIa/antagonists & inhibitors , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Blood Coagulation/drug effects , Crystallography, X-Ray , Factor VIIa/metabolism , Halogens/chemistry , Halogens/pharmacology , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Lactams/metabolism , Lactams/pharmacology , Models, Molecular , Molecular Docking SimulationABSTRACT
Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel anticoagulants that show excellent efficacy and minimal bleeding in preclinical models. On the basis of a zwitterionic phenylglycine acylsulfonamide 1, a phenylglycine benzylamide 2 was shown to possess improved permeability and oral bioavailability. Optimization of the benzylamide, guided by X-ray crystallography, led to a potent TF-FVIIa inhibitor 18i with promising oral bioavailability, but promiscuous activity in an in vitro safety panel of receptors and enzymes. Introducing an acid on the pyrrolidine ring, guided by molecular modeling, resulted in highly potent, selective, and efficacious TF-FVIIa inhibitors with clean in vitro safety profile. The pyrrolidine acid 20 showed a moderate clearance, low volume of distribution, and a short t 1/2 in dog PK studies.
ABSTRACT
Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P' binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype.
Subject(s)
Benzamidines , Factor VIIa/antagonists & inhibitors , Serine Proteinase Inhibitors/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Crystallography, X-Ray , Dose-Response Relationship, Drug , Factor VIIa/metabolism , Humans , Models, Molecular , Molecular Structure , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.
Subject(s)
Androgens , Muscles/drug effects , Muscles/metabolism , Oxazoles/chemistry , Oxazoles/pharmacology , Animals , Crystallography, X-Ray , Humans , Hydrogen-Ion Concentration , Male , Models, Molecular , Molecular Conformation , Prostate/drug effects , Prostate/metabolism , Rats , Substrate SpecificityABSTRACT
The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glucosides/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Kidney/metabolism , Sodium-Glucose Transporter 2 Inhibitors , Administration, Oral , Animals , Benzhydryl Compounds , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/drug therapy , Glucosides/chemistry , Glucosides/pharmacology , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Rats , Sodium-Glucose Transporter 2 , StereoisomerismABSTRACT
Replacement of the 3-oxo group of 2-chloro-4-[(7R,7aS)-7-hydroxy-1,3-dioxotetrahydro-1H-pyrrolo[1,2c]imidazol-2(3H)-yl]-3-methylbenzonitrile resulted in a sulfamide series of selective androgen receptor modulator (SARM) agonists.
Subject(s)
Androgens , Testosterone Congeners/chemical synthesis , Testosterone Congeners/pharmacology , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacology , Animals , Dose-Response Relationship, Drug , Male , Molecular Structure , Muscle, Skeletal/drug effects , Muscle, Skeletal/growth & development , Prostate/drug effects , Prostate/growth & development , Protein Binding , Rats , Receptors, Androgen/metabolism , Structure-Activity RelationshipABSTRACT
A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR Ki = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.
