A5060500115- Pain Mechanisms and Treatments
- Ion channel regulation and function
- Adipose Tissue and Metabolism
- Cholinesterase and Neurodegenerative Diseases
- Diet and metabolism studies
- Muscle metabolism and nutrition
- Mitochondrial Function and Pathology
- Pharmacological Receptor Mechanisms and Effects
- Neuroscience and Neuropharmacology Research
- Regulation of Appetite and Obesity
- Neuropeptides and Animal Physiology
- Biochemical Analysis and Sensing Techniques
- Pharmacological Effects and Toxicity Studies
- Pancreatic function and diabetes
- Coordination Chemistry and Organometallics
- Metabolism, Diabetes, and Cancer
- melanin and skin pigmentation
- Hormonal and reproductive studies
- Chemical synthesis and alkaloids
- Urologic and reproductive health conditions
- Hypothalamic control of reproductive hormones
- Cannabis and Cannabinoid Research
- Zebrafish Biomedical Research Applications
- Sexual function and dysfunction studies
- Burn Injury Management and Outcomes
Oregon State University
2020-2024
Boston University
2017-2019
Merck & Co., Inc., Rahway, NJ, USA (United States)
2002-2014
Merck (Japan)
2009
Oregon National Primate Research Center
2001
Oregon Health & Science University
2001
Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic stimulate erectile activity. We report the design development of 1, a potent, selective (1184-fold vs MC3R, 350-fold MC5R), small-molecule agonist MC4 receptor. Pharmacological testing confirms food intake lowering effects MC4R agonism suggests another role for in stimulation
Voltage-gated calcium channel (Ca(v))2.2 (N-type channels) are key components in nociceptive transmission pathways. Ziconotide, a state-independent peptide inhibitor of Ca(v)2.2 channels, is efficacious treating refractory pain but exhibits narrow therapeutic window and must be administered intrathecally. We have discovered an N-triazole oxindole, (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1), as...
The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2- phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine) salt, 11. Incubation 11 rat, dog, and human plasma hepatic subcellular fractions vitro indicated that conversion to would be expected occur vivo most readily humans during circulation. Conversion occurred...
Aerobic training stimulates mitochondrial metabolism in skeletal muscle that is linked to improvements whole body fuel metabolism. The mechanisms driving changes the quantity and quality (function per unit) of mitochondria are less known. We used seven sessions high-intensity interval (HIIT) determine functional remodeling muscle. HIIT increased respiration mass for fatty acids, complex I, II substrates. HIIT-induced pathways including gene transcripts (via RNA sequencing tissue) proteins...
Voltage-gated sodium channels (Na(v)1) are expressed in primary sensory neurons where they influence excitability via their role the generation and propagation of action potentials. Recently, human genetic data have shown that one channel subtype, Na(v)1.7, plays a major pain. We performed these studies to characterize antinociceptive effects...
We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing FAAH inhibition in vitro potency, improving pharmacokinetic (PK) profile, increasing vivo efficacy rodent inflammatory neuropathic pain assays.
Several sodium channel blockers are used clinically to treat neuropathic pain. However, many patients fail achieve adequate pain relief from these highly brain-penetrant drugs because of dose-limiting central nervous system side effects. Here, we describe the functional properties <i>trans</i>-<i>N</i>-{[2′-(aminosulfonyl)biphenyl-4-yl]methyl}-<i>N</i>-methyl-<i>N</i>′-[4-(trifluoromethoxy)benzyl]cyclopentane-1,2-dicarboxamide (CDA54), a peripherally acting blocker. In whole-cell...
The voltage-gated calcium channel Ca(v)2.2 (N-type channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment chronic pain. We report here discovery sulfonamide-derived, state-dependent inhibitors Ca(v)2.2. In particular, 19 inhibitor that selective over cardiac ion channels, with good preclinical PK biodistribution profile. This compound exhibits dose-dependent efficacy in models inflammatory hyperalgesia neuropathic allodynia devoid...
Chronic high caloric intake (HCI) is a risk factor for multiple major human disorders, from diabetes to neurodegeneration. Mounting evidence suggests significant contribution of circadian misalignment and sleep alterations this phenomenon. An inverse temporal relationship between sleep, activity, food intake, clock mechanisms in nocturnal diurnal animals that search effective therapeutic approaches can benefit the use animal models. Here, we show that, similar normal aging, HCI leads...
Extensive development of the structure−activity relationships a screening lead determined three important pharmacophores for gonadotropin-releasing hormone (GnRH) receptor antagonist activity. Incorporation 3,4,5-trimethylphenyl group at 3-position, 2-(2(S)-azetidinyl)ethoxy 4-position, and N-4-pyrimidinylcarboxamide 6-position quinolone core resulted in identification 4-(2-(azetidin-2(S)-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxylic acid...
We report the investigation of sulfonamide-derived Cav2.2 inhibitors to address drug-metabolism liabilities with this lead class analgesics. Modification benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation persistent 3-(trifluoromethyl)benzenesulfonamide metabolite was an endemic problem sulfonamide series replacement center aminopiperidine scaffold failed prevent metabolic pathway. This issue eventually addressed by application...