A5067824817- Adenosine and Purinergic Signaling
- Receptor Mechanisms and Signaling
- Synthesis and Biological Evaluation
- Synthesis and Catalytic Reactions
- Cardiac electrophysiology and arrhythmias
- Chronic Lymphocytic Leukemia Research
- PI3K/AKT/mTOR signaling in cancer
- Monoclonal and Polyclonal Antibodies Research
- Eicosanoids and Hypertension Pharmacology
- Toxin Mechanisms and Immunotoxins
- Organic Chemistry Cycloaddition Reactions
- Cell Adhesion Molecules Research
- Nicotinic Acetylcholine Receptors Study
- X-ray Diffraction in Crystallography
- Cardiac Arrhythmias and Treatments
- Nitric Oxide and Endothelin Effects
- Chemical Synthesis and Analysis
- Synthesis and Characterization of Heterocyclic Compounds
- Carbohydrate Chemistry and Synthesis
- Ion channel regulation and function
- Asymmetric Synthesis and Catalysis
- Pharmacological Receptor Mechanisms and Effects
- Mast cells and histamine
- Cholinesterase and Neurodegenerative Diseases
- Crystallization and Solubility Studies
Lupin Pharmaceuticals (India)
2019-2023
Carolina Veterinary Specialists
2001-2005
Several potent and selective A2A adenosine receptor agonists are currently available. These compounds have a high affinity for the long duration of action. However, in situations where short action is desired, available less than ideal. From series recently synthesized agonists, two (CVT-3146 CVT-3033) with low were selected further characterization as short-acting coronary vasodilators. Both (AdoR) versus A1, A2B, A3AdoR binding functional studies. CVT-3146 CVT-3033 appeared to be weak...
Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is believed be an A(2B) adenosine receptor (AdoR) mediated pathway. We hypothesize that a selective, high-affinity AdoR antagonist may provide therapeutic benefit the treatment of asthma. In attempt identify high-affinity, selective for AdoR, we synthesized 8-(C-4-pyrazolyl) xanthines. Compound 22, 8-(1H-pyrazol-4-yl)-1,3-dipropyl xanthine, N-1 unsubstituted pyrazole derivative favorable binding...
The use of full agonists the A 1 -adenosine receptor (A -ADOR) as antiarrhythmic agents is limited by their actions to cause high-grade atrioventricular (AV) block, profound bradycardia, atrial fibrillation, and vasodilation. It may be possible avoid these undesired partial agonists. We determined effects CVT-2759, a potential agonist -ADORs, on guinea pig hearts. CVT-2759 (0.1–100 μM) increased S-H interval isolated heart from 45 ± 60 3 ms ( P < 0.01) with half-maximal effect at 3.1 μM....
<i>Background:</i> Intracellular cyclic adenosine monophosphate (cAMP) in inflammatory cells and airway smooth muscle is critical to the modulation of response generation. Phosphodiesterase 4 (PDE4), an enzyme that catalyzes cAMP degradation, therefore being actively explored as a molecular target for treatment inflammation, particularly asthma chronic obstructive pulmonary disease. The field has undergone major advances optimizing generation compounds with safe therapeutic...
Our initial structure–activity relationship studies on 7-methoxy-4-morpholino-benzothiazole derivatives featured by aryloxy-2-methylpropanamide moieties at the 2-position led to identification of compound 25 as a potent and selective A2A adenosine receptor (A2AAdoR) antagonist with reasonable ADME pharmacokinetic properties. However, poor intrinsic solubility low moderate oral bioavailability made this series unsuitable for further development. Further optimization using structure-based drug...
The discovery of a series thiophenephenylsulfonamides as positive allosteric modulators (PAM) α7 nicotinic acetylcholine receptor (α7 nAChR) is described. Optimization this led to identification compound 28, novel PAM nAChR). Compound 28 showed good in vitro potency, with pharmacokinetic profile across species excellent brain penetration and residence time. robustly reversed the cognitive deficits episodic/working memory both time-delay scopolamine-induced amnesia paradigms object social...
We describe the synthesis of new high affinity and selective A3-adenosine receptor (A3-AdoR) agonists. Introduction a methyl group at N6-position A2A-AdoR 2-pyrazolyl-adenosine analogues (Figure 2) brought about substantial increase in A3-AdoR binding selectivity. While N6-desmethyl 3a 4 were inactive (Ki > 10 μM), corresponding N6-methyl 5 22 showed good = 73 97 nM, respectively). Replacement carboxamide with different heteroaryl groups resulted affinities selectivity for A3-AdoR....
Compound 20 (CVT-3146--a 2-[(N-1-(4-N-methylcarboxamidopyrazolyl)] adenosine derivative) and compound 31 (CVT-3033--a 2-[(4-(1-N-pentylpyrazolyl)] derivative), were found to be short acting functionally selective coronary vasodilators (CV t0.5 = 5.2 +/- 0.2 3.4 0.5 min, respectively--rat isolated heart 50% reversal time) with good potency (EC50S 6.4 1.2 nM 67.9 16.7 nM, respectively), but they possess low affinity for the ADO A2A receptor (Ki 1122 323 2138 952 respectively; pig striatum).
l-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as candidate gene for blood pressure quantitative trait locus rats. To investigate pharmacological role of management pressure, selective inhibitors were developed. Optimization screening hits 1 2 led to discovery compounds 3 4 potent rat pharmacokinetic properties suitable vivo studies Treatment compound or resulted significant reduction attenuation an...
PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a inhibitor that overcomes all these deficiencies, pharmacophoric expansion strategy was employed. Herein, we describe systematic transformation "three-blade propeller" shaped lead,...
Adenosine A2A receptor (A2AAdoR) antagonism is a nondopaminergic approach to Parkinson's disease treatment that under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as A2AAdoR antagonists. We herein described novel series [1,2,4]triazolo[5,1-f]purin-2-one displays functional with high degree selectivity over A1, A2B, and A3 receptors. Compounds from this new scaffold resulted in discovery highly potent, selective, stable,...
Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of inhibitors with all the desired properties to develop as an oral therapeutic pain has been major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out identify novel sulfonamide derivatives potent, selective, and state-dependent Scaffold hopping from benzoxazine chroman indane bicyclic system followed by thiazole replacement on led identification lead...
The calcium sensing receptor (CaSR) plays an important role in maintaining homeostasis. use of calcimimetic cinacalcet has been established to activate CaSR and normalize hypercalcemia. However, limitations due its high cLogP pKa. A systematic optimization reduce pKa yielded compound 23a (LNP1892). Compound showed excellent potency a favorable pharmacokinetics profile, lacked the liabilities cinacalcet, making it highly differentiated precision calcimimetic. In adenine-diet-induced chronic...