ABSTRACT
Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by low levels of functional survival motor neuron protein (SMN) resulting from a deletion or loss of function mutation of the survival motor neuron 1 (SMN1) gene. Branaplam (1) elevates levels of full-length SMN protein in vivo by modulating the splicing of the related gene SMN2 to enhance the exon-7 inclusion and increase levels of the SMN. The intramolecular hydrogen bond present in the 2-hydroxyphenyl pyridazine core of 1 enforces a planar conformation of the biaryl system and is critical for the compound activity. Scaffold morphing revealed that the pyridazine could be replaced by a 1,3,4-thiadiazole, which provided additional opportunities for a conformational constraint of the biaryl through intramolecular 1,5-sulfur-oxygen (S···O) or 1,5-sulfur-halogen (S···X) noncovalent interactions. Compound 26, which incorporates a 2-fluorophenyl thiadiazole motif, demonstrated a greater than 50% increase in production of full-length SMN protein in a mouse model of SMA.
Subject(s)
Drug Design , RNA Splicing , Thiadiazoles/chemistry , Animals , Half-Life , Halogens/chemistry , Humans , Male , Mice , Molecular Conformation , Motor Neurons/metabolism , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/pathology , Oxygen/chemistry , Pyridazines/chemistry , RNA Splicing/drug effects , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfur/chemistry , Survival of Motor Neuron 1 Protein/genetics , Survival of Motor Neuron 1 Protein/metabolism , Survival of Motor Neuron 2 Protein/genetics , Survival of Motor Neuron 2 Protein/metabolism , Thiadiazoles/metabolism , Thiadiazoles/pharmacologyABSTRACT
Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.
Subject(s)
Brain/drug effects , ERG1 Potassium Channel/metabolism , Muscular Atrophy, Spinal/drug therapy , Pyridazines/chemistry , Administration, Oral , Animals , Brain/metabolism , Cell Line , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , ERG1 Potassium Channel/antagonists & inhibitors , Humans , Mice, Inbred C57BL , Motor Neurons/drug effects , Muscular Atrophy, Spinal/genetics , Pyridazines/pharmacology , Quantitative Structure-Activity Relationship , RNA Splicing , Rats, Sprague-Dawley , Survival of Motor Neuron 1 Protein/genetics , Survival of Motor Neuron 1 Protein/metabolism , Survival of Motor Neuron 2 Protein/geneticsABSTRACT
High DGAT1 expression levels in the small intestine highlight the critical role this enzyme plays in nutrient absorption. Identification of inhibitors which predominantly inhibit DGAT1 in the gut is an attractive drug discovery strategy with anticipated benefits of reduced systemic toxicity. In this report we describe our discovery and optimization of DGAT1 inhibitors whose plasma exposure is minimized by the action of transporters, including the P-glycoprotein transporter. The impact of this unique absorption profile on efficacy in rat and dog efficacy models is presented.
ABSTRACT
Identification and structure-guided optimization of a series of 4-(pyrazol-4-yl)-pyrimidines as selective CDK4/6 inhibitors is reported herein. Several potency and selectivity determinants were established based on the X-ray crystallographic analysis of representative compounds bound to monomeric CDK6. Significant selectivity for CDK4/6 over CDK1 and CDK2 was demonstrated with several compounds in both enzymatic and cellular assays.
Subject(s)
Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Models, Molecular , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Cell Line, Tumor , Crystallography, X-Ray , Cyclin-Dependent Kinase 4/chemistry , Cyclin-Dependent Kinase 6/chemistry , High-Throughput Screening Assays , Humans , Kinetics , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity RelationshipABSTRACT
[reaction: see text] In connection with the known diyne-ene [2 + 2 + 2] cycloaddition reactions mediated by titanium aryloxides, the ability of titanium alkoxides to promote coupling of a titanacyclopentadiene with an alkene has been assessed for the isomerization-free preparation of 1,3-cyclohexadienes. The successful cycloaddition by titanium alkoxides is predicated on the use of homoallylic alcohols as the olefin component. With secondary homoallylic alcohols, high 1,3-diastereoselectivity is observed, which lends itself to enantioselective preparation of functionalized 1,3-cyclohexadienes.
Subject(s)
Alcohols/chemical synthesis , Alkynes/chemistry , Allyl Compounds/chemical synthesis , Titanium/chemistry , Allyl Compounds/chemistry , Cyclization , Cyclopropanes/chemistry , Hydrocarbons, Cyclic/chemical synthesis , Organometallic Compounds/chemistry , StereoisomerismABSTRACT
Starting with the tricyclic core 2b, annulation to form the 13-membered western ring of sarain A has been achieved to afford the macrocycle 30a by initial construction of the sterically congested quaternary center at C-3, followed by elaboration of the C-3 side-chain and ring-closing olefin metathesis. Also included is a parallel conversion of tricycle 2c to macrocycle 30b containing a functionalized side-chain at N-1 suitable for attachment of the eastern macrocyclic ring.
