ABSTRACT
Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chemistry and pharmacological studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clinical trials.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , beta-N-Acetylhexosaminidases/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Brain/drug effects , Dogs , Drug Discovery , Enzyme Inhibitors/blood , Enzyme Inhibitors/pharmacokinetics , Humans , Macaca mulatta , Male , PC12 Cells , Rats , Rats, Wistar , Structure-Activity Relationship , Tauopathies/drug therapy , beta-N-Acetylhexosaminidases/chemistry , beta-N-Acetylhexosaminidases/metabolismABSTRACT
The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
Subject(s)
Anti-HIV Agents/pharmacology , Benzoates/pharmacology , CCR5 Receptor Antagonists , Virus Replication/drug effects , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Benzoates/chemical synthesis , Benzoates/chemistry , CHO Cells , Cell Survival/drug effects , Cells, Cultured , Cricetinae , Cricetulus , Drug Design , HEK293 Cells , HIV-1/drug effects , HIV-1/physiology , Host-Pathogen Interactions/drug effects , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Imidazolidines/chemistry , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/virology , Models, Chemical , Molecular Structure , Piperidines/chemistry , Receptors, CCR5/genetics , Receptors, CCR5/metabolism , Structure-Activity RelationshipABSTRACT
The condensation of aldehydes and ketones with hydroxylamine hydrochloride results oximes in 50.7-98.7% yields in EtOH under ultrasound irradiation. Compared with conventional methods, the main advantages of the present procedure are milder conditions, shorter reaction time and higher yields.
ABSTRACT
An efficient and convenient approach to the synthesis of 3,3,6,6-tetramethyl-9-aryl-1,8-dioxo-octahydroxanthene derivatives using p-dodecylbenzenesulfonic acid (DBSA) as the catalyst (10 mol.%) under ultrasound irradiation is described. This method provides several advantages such as environment friendliness, high yields and simple work-up procedure. In addition, water was chosen as a green solvent.
ABSTRACT
Synthesis of bis(indolyl)methanes via electrophilic substitution reactions of indoles with aromatic aldehydes and ketones catalyzed by aminosulfonic acid was carried out in 23-96% yield at 30-38 degrees C in EtOH aqueous solution under ultrasound irradiation.
Subject(s)
Indoles/chemistry , Methane/chemistry , Sonication , Sulfonic Acids/chemistry , Catalysis , Indoles/radiation effects , Methane/radiation effects , Sulfonic Acids/radiation effectsABSTRACT
1,1-Disubstituted-2,6-diarylcyclohexane-4-ones have been synthesized via double Michael addition of 1,5-diaryl-1,4-pentadien-3-one with various active methylene compounds such as dimethyl malonate, diethyl malonate, methyl cyanoacetate and ethyl cyanoacetate catalyzed by KF/basic alumina under ultrasound irradiation to give good yields within a short time.
ABSTRACT
Titanium trichloride in EtOH can be reduced by Mg to the corresponding low valent titanium complexes, which can reduce some aromatic aldehydes and ketones to the corresponding pinacols in 8-95% yields within 15-40 min under ultrasound irradiation.
ABSTRACT
A general and practical synthetic route to 2-amino-2-chromenes in water in the presence of cetyltrimethylammonium bromide (CTABr) as catalyst is described under ultrasound irradiation.
ABSTRACT
The condensation of aldehydes, beta-keto esters and urea catalyzed by NH(2)SO(3)H in ethanol results dihydropyrimidinones in high yields under ultrasound irradiation.
ABSTRACT
Synthesis of 2-aroyl-1,3,5-triaryl-4-carbethoxy-4-cyanocyclohexanols from chalcones with ethyl cyanoacetate is carried out in excellent yields with KF/basic alumina as catalyst under ultrasound irradiation.
ABSTRACT
The Michael reaction of chalcones as acceptors with various active methylene compounds such as diethyl malonate, nitromethane, cyclohexanone, ethyl acetoacetate and acetylacetone as donors catalyzed by KF/basic alumina results in adducts in high yield within a shorter time under ultrasound irradiation.
ABSTRACT
Claisen-Schmidt condensation of acetophenone with aromatic aldehydes catalyzed by pulverized KOH and KF-Al2O3 results chalcones in 52-97% and 83-98% yields respectively in alcoholic solvent under ultrasound irradiation.
Subject(s)
Chalcone/analogs & derivatives , Chalcone/chemical synthesis , Ultrasonography , Aldehydes/chemistry , Aluminum Oxide/chemistry , Catalysis , Hydroxides/chemistry , Potassium Compounds/chemistryABSTRACT
Knoevenagel condensation of ethyl cyanoacetate with aromatic aldehyde catalyzed by KF-Al2O3 in ethanol results ethyl alpha-cyanocinnamates in 97-99% yield under ultrasound irradiation.
