ABSTRACT
Adult rats were treated acutely with peripheral kainic acid (KA), and changes in brain-derived neurotrophic factor (BDNF) mRNA and protein were tracked over time across multiple brain regions. Despite robust elevation in both mRNA and protein in multiple brain regions, plasma BDNF was unchanged and cerebrospinal fluid (CSF) BDNF levels remained undetectable. Primary neurons were then treated with KA. BDNF was similarly elevated within neurons, but was undetectable in neuronal media. Thus, while deficits in BDNF signaling have been implicated in a number of diseases, these data suggest that extracellular concentrations of BDNF may not be a facile biomarker for changes in neurons.
Subject(s)
Brain-Derived Neurotrophic Factor/blood , Brain-Derived Neurotrophic Factor/genetics , Gene Expression , Hippocampus/metabolism , Animals , Brain/metabolism , Brain/pathology , Brain-Derived Neurotrophic Factor/cerebrospinal fluid , Brain-Derived Neurotrophic Factor/metabolism , Cells, Cultured , Choroid Plexus/pathology , Hippocampus/pathology , Humans , Kainic Acid , L-Lactate Dehydrogenase/metabolism , Male , Neurons/enzymology , Neurons/metabolism , Primary Cell Culture , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Seizures/blood , Seizures/cerebrospinal fluid , Seizures/chemically inducedABSTRACT
A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFß receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFß induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.
Subject(s)
Cicatrix/prevention & control , Drug Discovery , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Skin/drug effects , Animals , Models, Molecular , Phosphorylation , Rats , Receptor, Transforming Growth Factor-beta Type IABSTRACT
The cognitive impairments observed in Alzheimer's disease (AD) are in part a consequence of reduced acetylcholine (ACh) levels resulting from a loss of cholinergic neurons. Preclinically, serotonin 4 receptor (5-HT(4)) agonists are reported to modulate cholinergic function and therefore may provide a new mechanistic approach for treating cognitive deficits associated with AD. Herein we communicate the design and synthesis of potent, selective, and brain penetrant 5-HT(4) agonists. The overall goal of the medicinal chemistry strategy was identification of structurally diverse clinical candidates with varying intrinsic activities. The exposure-response relationships between binding affinity, intrinsic activity, receptor occupancy, drug exposure, and pharmacodynamic activity in relevant preclinical models of AD were utilized as key selection criteria for advancing compounds. On the basis of their excellent balance of pharmacokinetic attributes and safety, two lead 5-HT(4) partial agonist candidates 2d and 3 were chosen for clinical development.
Subject(s)
Alzheimer Disease/drug therapy , Cognition Disorders/drug therapy , Indoles/chemical synthesis , Piperidines/chemical synthesis , Pyrans/chemical synthesis , Serotonin 5-HT4 Receptor Agonists/chemical synthesis , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Alzheimer Disease/psychology , Animals , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP/biosynthesis , Dogs , Drug Partial Agonism , HEK293 Cells , Haplorhini , Humans , In Vitro Techniques , Indoles/pharmacokinetics , Indoles/pharmacology , Madin Darby Canine Kidney Cells , Male , Microsomes, Liver/metabolism , Permeability , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protein Isoforms/metabolism , Pyrans/pharmacokinetics , Pyrans/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Serotonin, 5-HT4/metabolism , Serotonin 5-HT4 Receptor Agonists/pharmacokinetics , Serotonin 5-HT4 Receptor Agonists/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
4-((1 R,2 R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)- 6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (-)- 6a was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.