A5066442460- Alzheimer's disease research and treatments
- Drug Transport and Resistance Mechanisms
- Computational Drug Discovery Methods
- Angiogenesis and VEGF in Cancer
- PI3K/AKT/mTOR signaling in cancer
- Urinary Bladder and Prostate Research
- Phenothiazines and Benzothiazines Synthesis and Activities
- Synthesis and Catalytic Reactions
- Cholinesterase and Neurodegenerative Diseases
- Bioactive Compounds and Antitumor Agents
- Receptor Mechanisms and Signaling
- HER2/EGFR in Cancer Research
- Coordination Chemistry and Organometallics
- Enzyme function and inhibition
- Chronic Myeloid Leukemia Treatments
- Protein Kinase Regulation and GTPase Signaling
- Quinazolinone synthesis and applications
- Nitric Oxide and Endothelin Effects
- Carbon dioxide utilization in catalysis
- Sulfur-Based Synthesis Techniques
- Neurobiology and Insect Physiology Research
- Organometallic Complex Synthesis and Catalysis
- Chemical Synthesis and Analysis
- Adenosine and Purinergic Signaling
- Neuroendocrine regulation and behavior
Amgen (United States)
2008-2018
University of Palermo
1997
University of New Hampshire
1995
Because of its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment pain. We have previously reported on number structurally distinct bicyclic heteroarylsulfonamides inhibitors that demonstrate high levels selectivity over other NaV isoforms. Herein, we report discovery and optimization series atropisomeric quinolinone sulfonamide [ Bicyclic compounds sodium channel their preparation . WO 2014201206, 2014 ] NaV1.7, which nanomolar inhibition...
A structure- and property-based drug design approach was employed to identify aminooxazoline xanthenes as potent selective human β-secretase inhibitors. These compounds exhibited good isolated enzyme, cell potency, selectivity against the structurally related aspartyl protease cathepsin D. Our efforts resulted in identification of a potent, orally bioavailable CNS penetrant compound that vivo efficacy. single oral dose 11a significant reduction Aβ40 naive rats.
A series of potent hydroxyethyl amine (HEA) derived inhibitors β-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a benzodioxolane analogues that possessed improved metabolic stability increased oral bioavailability. Subsequent efforts focused on improving exposure by limiting susceptibility Pgp-mediated efflux an inhibitor which demonstrated robust sustained reduction β-amyloid (Aβ) in Sprague–Dawley rats...
There has been significant interest in developing a transient receptor potential A1 (TRPA1) antagonist for the treatment of pain due to wealth data implicating its role pathways. Despite this, identification potent small molecule tool possessing pharmacokinetic properties allowing robust vivo target coverage challenging. Here we describe optimization potent, selective series quinazolinone-based TRPA1 antagonists. High-throughput screening identified 4, which possessed promising potency and...
Several reports have recently emerged regarding the identification of heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels selectivity over other NaV isoforms. The optimization a series internal leads address number metabolic liabilities including bioactivation, PXR activation, well CYP3A4 induction and inhibition led to potent selective demonstrated favorable pharmacokinetic profiles were devoid aforementioned liabilities. key achieving this within prone...
Angiogenesis is vital for solid tumor growth, and its prevention a proven strategy the treatment of disease states such as cancer. The vascular endothelial growth factor (VEGF) pathway provides several opportunities by which small molecules can act inhibitors proliferation migration. Critical to these processes signaling through VEGFR-2 or kinase insert domain receptor (KDR) upon stimulation ligand VEGF. Herein, we report discovery 2,3-dihydro-1,4-benzoxazines intrinsic KDR activity (IC 50 <...
A series of naphthyl-based compounds were synthesized as potential inhibitors vascular endothelial growth factor (VEGF) receptors. Investigations structure-activity relationships led to the identification a naphthamides that are potent VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition VEGF-dependent human umbilical vein cell (HUVEC) proliferation, and these several possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48...
A structurally novel series of adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channel openers is described. As part our efforts directed toward identifying novel, bladder-selective (KCOs) targeted for urge urinary incontinence (UUI), we found that bioisosteric replacement the N-cyanoguanidine moiety pinacidil (1, Figure 1) with a diaminocyclobutenedione template afforded squaric acid analogue 2, prototype K(ATP) unique selectivity bladder smooth muscle in vivo. Further modification...
We have previously shown that hydroxyethylamines can be potent inhibitors of the BACE1 enzyme and generation with CYP 3A4 inhibitory activities in this scaffold affords compounds (e.g., 1) sufficient bioavailability pharmacokinetic profiles to reduce central amyloid-β peptide (Aβ) levels wild-type rats following oral dosing. In article, we describe further modifications P1-phenyl ring hydroxyethylamine series afford potent, dual BACE1/CYP which demonstrate improved penetration into CNS....
Regioselective N-alkylation of 1,3-azoles is a valuable transformation. Organomagnesium reagents were discovered to be competent bases affect regioselective alkylation various 1,3-azoles. Counterintuitively, substitution selectively occurred at the more sterically hindered nitrogen atom. Numerous examples are provided, on varying 1,3-azole scaffolds, with yields ranging from 25 95%.
A novel series of benzylamine, potassium channel openers (KCOs) is presented as part our program toward designing new, bladder-selective compounds for the treatment urge urinary incontinence (UUI). We have found that in vitro potency (R)-4-[3,4-dioxo-2-(1,2, 2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzo nitrile 1 relaxation precontracted rat detrusor strips can also be obtained with cyanobenzylamine derivative 4 (IC(50) = 0.29 microM) (Figure 3). Addition a 2-Cl substituted...
We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared found to yield nanomolar VEGFR-2 (KDR) with an improved selectivity profile against a panel tyrosine serine/threonine kinases. The inhibitory activity this series was retained at the cellular level. Naphthamides 3, 20, 22 exhibited good pharmacokinetics following oral dosing showed inhibition VEGF-induced...
β-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted hydroxyethylamine-derived such as 1 with low nanomolar potency against β-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound was also shown to significantly reduce Aβ40 levels plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led the discovery of inhibitor 16 a novel, potent,...
Sera and urine samples from 115 Sicilian patients with boutonneuse fever (BF), obtained at the time of diagnosis after clinical recovery, were analyzed for concentrations interleukin (IL)-2 soluble IL-2 receptor (sIL-2R). There significantly high levels sIL-2R in sera acute BF compared healthy controls, values returned to normal following successful chemotherapy. The data indicate that correlated directly levels. In contrast, all tested samples, normal. Furthermore, a reduction production by...
Abstract 1,3‐Azoles and various derivatives thereof, including substituted 1,3‐benzodiazoles, purines, imidazopyridines, are efficiently alkylated following a protecting group‐free strategy.
Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is the most common form of dementia affecting 4-8% elderly population worldwide. Aggregation core constituent amyloid plaques, Aß believed to play critical role in pathology AD. The aspartyl protease, beta-site precursor protein cleaving enzyme (BACE1), catalyses rate-limiting step production Aβ and therefore considered be an important target for drug development In vitro potency: Enzyme IC 50s were measured using...