ABSTRACT
A novel series of N-type calcium channel inhibitors have been discovered. Optimization of potency and HT-ADME properties provides 4-aminocyclopentapyrrolidines with analgesic efficacy after oral dosing.
Subject(s)
Analgesics/chemistry , Analgesics/therapeutic use , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/therapeutic use , Calcium Channels, N-Type/metabolism , Neuralgia/drug therapy , Administration, Oral , Analgesics/chemical synthesis , Analgesics/metabolism , Animals , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/metabolism , Humans , Microsomes/metabolism , Rats , Structure-Activity RelationshipABSTRACT
A series of symmetry-based HIV protease inhibitors was designed and synthesized. Modification of the core regiochemistry and stereochemistry significantly affected the potency, metabolic stability, and oral bioavailability of the inhibitors, as did the variation of a pendent arylmethyl P3 group. Optimization led to the selection of two compounds, 10c (A-790742) and 9d (A-792611), for advancement to preclinical studies. Both compounds displayed low nanomolar potency against wild type HIV in the presence of human serum, low rates of metabolism in human liver microsomes, and high oral bioavailability in animal models. The compounds were examined in a preclinical model for the hyperbilirubinemia observed with some HIV PIs, and both exhibited less bilirubin elevation than comparator compounds. X-ray crystallographic analyses of the new cores were used to examine differences in their binding modes. The antiviral activity of the compounds against protease inhibitor resistant strains of HIV was also determined.
Subject(s)
Carbamates/chemical synthesis , Dipeptides/chemical synthesis , HIV Protease Inhibitors/chemical synthesis , Putrescine/analogs & derivatives , Pyridines/chemical synthesis , Animals , Binding Sites , Biological Availability , Caco-2 Cells , Carbamates/metabolism , Carbamates/pharmacology , Cell Membrane Permeability , Crystallography, X-Ray , Dipeptides/adverse effects , Dipeptides/pharmacology , Dogs , Drug Resistance, Viral , HIV Protease/genetics , HIV Protease Inhibitors/adverse effects , HIV Protease Inhibitors/pharmacology , HIV-1/drug effects , HIV-1/enzymology , HIV-1/genetics , Humans , Hyperbilirubinemia/chemically induced , Hyperlipidemias/chemically induced , Hyperlipidemias/metabolism , In Vitro Techniques , Microsomes, Liver/metabolism , Models, Molecular , Mutation , Putrescine/chemical synthesis , Putrescine/metabolism , Putrescine/pharmacology , Pyridines/adverse effects , Pyridines/pharmacology , Rats , Rats, Gunn , Stereoisomerism , Structure-Activity RelationshipABSTRACT
As a continuation of the recently communicated discovery of oximinoarylsulfonamides as potent inhibitors of HIV-1 aspartyl protease, compounds bearing pyridylmethyl substituents at P3 were designed and synthesized. Potent analogs in this series provided low single-digit nanomolar EC50 values against both wild-type HIV and resistant mutant virus (A17), attenuated some 3- to 12-fold in the presence of 50% human serum. Pharmacokinetic results for compounds in this series showed good to excellent exposure when co-administered orally with an equal amount of ritonavir (5mg/kg each) in the rat, with average AUC >8 microg h/mL. Similar dosing in dog resulted in significantly lower plasma levels (average AUC <2 microg h/mL). The 3-pyridylmethyl analog 30 gave the best overall exposure (rat AUC=7.1 microg h/mL and dog AUC=4.9 microg h/mL), however, this compound was found to be a potent inhibitor of cytochrome P450 3A (Ki=2.4 nM).
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacokinetics , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Animals , Anti-HIV Agents/chemistry , Area Under Curve , Cytochrome P-450 CYP3A Inhibitors , Dogs , Drug Design , HIV Protease Inhibitors/chemistry , HIV-1/drug effects , Humans , Microbial Sensitivity Tests , Molecular Conformation , Pyridines/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
The need for a potent HIV protease inhibitor (PI) to combat emerging PI-resistant viruses is anticipated. Analogs formulated from the combination of structural fragments of Ritonavir, Lopinavir, and Amprenavir were synthesized. Analogs containing the oxime pharmacophore were found to have improved activities against both wild type and resistant (A17) viruses. The synthesis and structure-activity relationships (SAR) based upon the in vitro IC50 of this series of compounds are reported.
Subject(s)
HIV Protease Inhibitors/chemical synthesis , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Binding Sites , Carbamates , Drug Design , Furans , HIV Protease/chemistry , HIV Protease/metabolism , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , Kinetics , Lopinavir , Models, Molecular , Molecular Conformation , Pyrimidinones/chemistry , Ritonavir/chemistry , Sulfonamides/chemistryABSTRACT
Drug discovery efforts at Abbott Laboratories have led to the identification of influenza neuraminidase inhibitor A-315675 (1) as a candidate for development as an antiinfluenza drug. A convergent, stereoselective synthesis of this highly functionalized pyrrolidine is reported that utilizes pyrrolinone 2 as the key intermediate. The C5, C6 stereochemistry was established through a diastereoselective condensation of chiral imine compound 3 with silyloxypyrrole 4 to give pyrrolinone 2. The stereochemical outcome of this reaction depended critically on the choice of the imine functional group (FG), with tritylsulfenyl and (R)-toluenesulfinyl providing the desired products in good yields as crystalline intermediates. Conversion of pyrrolinone 2 into 1 was accomplished in seven subsequent steps, including Michael addition of cis-1-propenylcuprate at C4 and introduction of a cyano group as a carboxylic acid equivalent at C2.
