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1.
Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y 1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y 1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y 12 antagonist clopidogrel in rat efficacy/bleeding models. 相似文献
2.
A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X 7 receptor antagonist. Structure–activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X 7 antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies. 相似文献
3.
High throughput screening (HTS) of our compound file provided an attractive lead compound with modest P2X 7 receptor antagonist potency and high selectivity against a panel of receptors and channels, but also with high human plasma protein binding and a predicted short half-life in humans. Multi-parameter optimization was used to address the potency, physicochemical and pharmacokinetic properties which led to potent P2X 7R antagonists with good disposition properties. Compound 33 (CE-224,535) was advanced to clinical studies for the treatment of rheumatoid arthritis. 相似文献
4.
Modification of a series of P2Y 12 receptor antagonists by replacement of the ester functionality was aimed at minimizing the risk of in vivo metabolic instability and pharmacokinetic variability. The resulting ketones were then optimized for their P2Y 12 antagonistic and anticoagulation effects in combination with their physicochemical and absorption profiles. The most promising compound showed very potent antiplatelet action in vivo. However, pharmacodynamic–pharmacokinetic analysis did not reveal a significant separation between its anti-platelet and bleeding effects. The relevance of receptor binding kinetics to the in vivo profile is described. 相似文献
5.
A weak antagonist of the pyrimidinergic receptor P2Y 14 containing a dihydropyridopyrimidine core was identified through high-throughput screening. Subsequent optimization led to potent, non-UTP competitive antagonists and represent the first reported non-nucleotide antagonists of this receptor. Compound 18q was identified as a 10 nM P2Y 14 antagonist with good oral bioavailability and provided sufficient exposure in mice to be used as a tool for future in vivo studies. 相似文献
6.
Previously, we had disclosed a novel class of hNK 1 antagonists based on the 5,5-fused pyrrolidine core. These compounds displayed subnanomolar hNK 1 affinity along with good efficacy in a gerbil foot-tapping (GFT) model, but unfortunately they had low to moderate functional antagonist (IP-1) activity. To elaborate on the SAR of this class of hNK 1 compounds and to improve functional activity, we have designed and synthesized a new class of hNK 1 antagonist with a third fused ring. Compared to the 5,5-fused pyrrolidine class, these 5,5,5-fused tricyclic hNK 1 antagonists maintain subnanomolar hNK 1 binding affinity with highly improved functional IP-1 activity (<10% SP remaining). A fused tricyclic methyl, hydroxyl geminally substituted pyrrolizinone (compound 20) had excellent functional IP (<2% SP remaining), hNK 1 binding affinity, off-target selectivity, pharmacokinetic profile and in vivo activity. Complete inhibition of agonist activity was observed at both 0 and 24 h in the gerbil foot-tapping model with an ID 50 of 0.02 mpk at both 0 and 24 h, respectively. 相似文献
7.
The discovery of a highly potent and selective EP 4 antagonist MF-766 is discussed. This N-benzyl indole derivative exhibits good pharmacokinetic profile and unprecedented in vivo potency in the rat AIA model. 相似文献
8.
Our series of competitive antagonists against the G-protein coupled receptor P2Y 14 were found to be highly shifted in the presence of serum (>99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323-fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared ( 7a- 7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile. 相似文献
9.
This Letter describes our attempts to elaborate dually acting compounds possessing serotonin re-uptake transporter inhibitor and serotonin 5-HT 2C receptor antagonist properties. A novel series of 1,3-diphenylureas and N-phenylbenzamides have thus been prepared and evaluated. Based on its in vitro and in vivo activities, as well as pharmacokinetic profile, compound 16a was identified as a lead compound. The synthesis and structure–activity relationship of this series of compounds is presented herein. 相似文献
10.
A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency ( 14, CGRP Ki = 23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency ( 19, CGRP Ki = 0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species. 相似文献
11.
A series of octahydropyrrolo[3,4- c]pyrroles were synthesized and evaluated by orexin 1 and 2 receptor (OX 1 & 2 R) antagonists assays. Compound 14l with potent OXR antagonist activity and suitable pharmacokinetic behavior was chosen to be investigated in an EEG study, which demonstrated effects of sleep promotion comparable to Suvorexant. Furthermore, the di-fluro substituted analogs exhibited reduced hERG inhibition while maintaining moderate potency. 相似文献
12.
Blockade of the P2Y 1 receptor is important to the treatment of thrombosis with potentially improved safety margins compared with P2Y 12 receptor antagonists. Investigation of a series of urea surrogates of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy- N-neopentyl spiropiperidine indolinyl series as potent P2Y 1 receptor antagonists, among which compound 5a was the most potent and the first non-urea analog with platelet aggregation (PA) IC 50 less than 0.5 μM with 10 μM ADP. Several 2-amino-1,3,4-thiadiazole analogs such as 5b and 5f had a more favorable pharmacokinetic profile, such as higher Ctrough, lower Cl, smaller Vdss, and similar bioavailability compared with 3. 相似文献
13.
Here we describe the identification, structure–activity relationship and the initial pharmacological characterization of AFQ056/mavoglurant, a structurally novel, non-competitive mGlu5 receptor antagonist. AFQ056/mavoglurant was identified by chemical derivatization of a lead compound discovered in a HTS campaign. In vitro, AFQ056/mavoglurant had an IC 50 of 30 nM in a functional assay with human mGluR5 and was selective over the other mGluR subtypes, iGluRs and a panel of 238 CNS relevant receptors, transporter or enzymes. In vivo, AFQ056/mavoglurant showed an improved pharmacokinetic profile in rat and efficacy in the stress-induced hyperthermia test in mice as compared to the prototypic mGluR5 antagonist MPEP. The efficacy of AFQ056/mavoglurant in humans has been assessed in L-dopa induced dyskinesia in Parkinson’s disease and Fragile X syndrome in proof of principle clinical studies. 相似文献
14.
The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK 1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK 1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK 1 receptor antagonists had yet to be realized; therefore clinical evidence that NK 1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK 1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK 1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK 1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK 1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties. 相似文献
15.
The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB 1 receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB 1 antagonist with high predicted human oral bioavailability. 相似文献
17.
Structure-activity relationship (SAR) efforts around our initial lead compound 1 led to the identification of potent P2X 7 receptor antagonists with improved pharmacokinetic profiles. These compounds were potent and selective at the P2X 7 receptor in both human and rodent. Compound (entry 31) exhibited oral efficacy in the rat MIA and CCI pain models. 相似文献
18.
Rapid phosphoester hydrolysis of endogenous purine and pyrimidine nucleotides has challenged the characterization of the role of P2 receptors in physiology and pathology. Nucleotide phosphoester stabilization has been pursued on a number of medicinal chemistry fronts. We investigated the in vitro and in vivo stability and pharmacokinetics of prototypical nucleotide P2Y1 receptor (P2Y1R) agonists and antagonists. These included the riboside nucleotide agonist 2-methylthio-ADP and antagonist MRS2179, as well as agonist MRS2365 and antagonist MRS2500 containing constrained (N)-methanocarba rings, which were previously reported to form nucleotides that are more slowly hydrolyzed at the α-phosphoester compared with the ribosides. In vitro incubations in mouse and human plasma and blood demonstrated the rapid hydrolysis of these compounds to nucleoside metabolites. This metabolism was inhibited by EDTA to chelate divalent cations required by ectonucleotidases for nucleotide hydrolysis. This rapid hydrolysis was confirmed in vivo in mouse pharmacokinetic studies that demonstrate that MRS2365 is a prodrug of the nucleoside metabolite AST-004 (MRS4322). Furthermore, we demonstrate that the nucleoside metabolites of MRS2365 and 2-methylthio-ADP are adenosine receptor (AR) agonists, notably at A3 and A1ARs. In vivo efficacy of MRS2365 in murine models of traumatic brain injury and stroke can be attributed to AR activation by its nucleoside metabolite AST-004, rather than P2Y1R activation. This research suggests the importance of reevaluation of previous in vitro and in vivo research of P2YRs and P2XRs as there is a potential that the pharmacology attributed to nucleotide agonists is due to AR activation by active nucleoside metabolites. 相似文献
19.
Platelets contain at least five purinergic G protein-coupled receptors, e.g., the pro-aggregatory P2Y 1 and P2Y 12 receptors, a P2Y 14 receptor (GPR105) of unknown function, and anti-aggregatory A 2A and A 2B adenosine receptor (ARs), in addition to the ligand-gated P2X1 ion channel. Probing the structure–activity relationships
(SARs) of the P2X and P2Y receptors for extracellular nucleotides has resulted in numerous new agonist and antagonist ligands.
Selective agents derived from known ligands and novel chemotypes can be used to help define the subtypes pharmacologically.
Some of these agents have entered into clinical trials in spite of the challenges of drug development for these classes of
receptors. The functional architecture of P2 receptors was extensively explored using mutagenesis and molecular modeling,
which are useful tools in drug discovery. In general, novel drug delivery methods, prodrug approaches, allosteric modulation,
and biased agonism would be desirable to overcome side effects that tend to occur even with receptor subtype-selective ligands.
Detailed SAR analyses have been constructed for nucleotide and non-nucleotide ligands at the P2Y 1, P2Y 12, and P2Y 14 receptors. The thienopyridine antithrombotic drugs Clopidogrel and Prasugrel require enzymatic pre-activation in vivo and
react irreversibly with the P2Y 12 receptor. There is much pharmaceutical development activity aimed at identifying reversible P2Y 12 receptor antagonists. The screening of chemically diverse compound libraries has identified novel chemotypes that act as
competitive, non-nucleotide antagonists of the P2Y 1 receptor or the P2Y 12 receptor, and antithrombotic properties of the structurally optimized analogues were demonstrated. In silico screening at
the A 2A AR has identified antagonist molecules having novel chemotypes. Fluorescent and other reporter groups incorporated into ligands
can enable new technology for receptor assays and imaging. The A 2A agonist CGS21680 and the P2Y 1 receptor antagonist MRS2500 were derivatized for covalent attachment to polyamidoamine dendrimeric carriers of MW 20,000,
and the resulting multivalent conjugates inhibited ADP-promoted platelet aggregation. In conclusion, a wide range of new pharmacological
tools is available to control platelet function by interacting with cell surface purine receptors. 相似文献
20.
Mast cell degranulation affects many conditions, e.g., asthma and urticaria. We explored the potential role of the P2Y 14 receptor (P2Y 14R) and other P2Y subtypes in degranulation of human LAD2 mast cells. All eight P2YRs were expressed at variable levels in LAD2 cells (quantitative real-time RT-PCR). Gene expression levels of ADP receptors, P2Y 1R, P2Y 12R, and P2Y 13R, were similar, and P2Y 11R and P2Y 4R were highly expressed at 5.8- and 3.8-fold of P2Y 1R, respectively. Least expressed P2Y 2R was 40-fold lower than P2Y 1R, and P2Y 6R and P2Y 14R were ≤50 % of P2Y 1R. None of the native P2YR agonists alone induced β-hexosaminidase (β-Hex) release, but some nucleotides significantly enhanced β-Hex release induced by C3a or antigen, with a rank efficacy order of ATP > UDPG ≥ ADP >> UDP, UTP. Although P2Y 11R and P2Y 4R are highly expressed, they did not seem to play a major role in degranulation as neither P2Y 4R agonist UTP nor P2Y 11R agonists ATPγS and NF546 had a substantial effect. P2Y 1R-selective agonist MRS2365 enhanced degranulation, but ~1,000-fold weaker compared to its P2Y 1R potency, and the effect of P2Y 6R agonist 3-phenacyl-UDP was negligible. The enhancement by ADP and ATP appears mediated via multiple receptors. Both UDPG and a synthetic agonist of the P2Y 14R, MRS2690, enhanced C3a-induced β-Hex release, which was inhibited by a P2Y 14R antagonist, specific P2Y 14R siRNA and pertussis toxin, suggesting a role of P2Y 14R activation in promoting human mast cell degranulation. 相似文献
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