ABSTRACT
Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100Ć¢ĀĀÆnM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10Ć¢ĀĀÆmpkĆ¢ĀĀÆ=Ć¢ĀĀÆ0Ć¢ĀĀÆĀµMĆ¢ĀĀÆh; F%Ć¢ĀĀÆ=Ć¢ĀĀÆ0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10Ć¢ĀĀÆmpkĆ¢ĀĀÆ=Ć¢ĀĀÆ26Ć¢ĀĀÆĀµMĆ¢ĀĀÆh; F%Ć¢ĀĀÆ=Ć¢ĀĀÆ70).
Subject(s)
Antineoplastic Agents/pharmacology , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrrolidines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Rats , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Inhibition of neprilysin (NEP) is widely studied as a therapeutic target for the treatment of hypertension, heart failure, and kidney disease. Sacubitril/valsartan (LCZ696) is a drug approved to reduce the risk of cardiovascular death in heart failure patients with reduced ejection fraction. LBQ657 is the active metabolite of sacubitril and an inhibitor of NEP. Previously, we have reported the crystal structure of NEP bound with LBQ657, whereby we noted the presence of a subsite in S1' that has not been explored before. We were also intrigued by the zinc coordination made by one of the carboxylic acids of LBQ657, leading us to explore alternative linkers to efficiently engage zinc for NEP inhibition. Structure-guided design culminated in the synthesis of selective, orally bioavailable, and subnanomolar inhibitors of NEP. A 17-fold boost in biochemical potency was observed upon addition of a chlorine atom that occupied the newly found subsite in S1'. We report herein the discovery and preclinical profiling of compound 13, which paved the path to our clinical candidate.
ABSTRACT
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
The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.
ABSTRACT
[reaction: see text] An efficient synthetic route to the ABC tricyclic core of 1alpha-alkyldaphnanes has been developed. The conformational bias imparted by the C6-C9 oxo-bridge of BC-ring system 12 was used to elaborate the ABC-ring system precursor including the introduction of the beta-C5 hydroxyl group. A completely diastereoselective palladium-catalyzed enyne cyclization was then employed to establish the A-ring with a C1 appendage.