- Novel 3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]propanamides as selective agonists of human formyl-peptide receptor 2
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N-Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) that play critical roles in inflammatory reactions, and FPR-specific interactions can possibly be used to facilitate the resolution of pathological inflammatory reactions. We here report the synthesis and biological evaluation of six pairs of chiral ureidopropanamido derivatives as potent and selective formyl peptide receptor-2 (FPR2) agonists that were designed starting from our lead agonist (S)-3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]-N-[[1-(5-methoxy-2-pyridinyl)cyclohexyl]methyl]propanamide ((S)-9a). The new compounds were obtained in overall yields considerably higher than (S)-9a. Several of the new compounds showed agonist properties comparable to that of (S)-9a along with higher selectivity over FPR1. Molecular modeling was used to define chiral recognition by FPR2. In vitro metabolic stability of selected compounds was also assessed to obtain preliminary insight on drug-like properties of this class of compounds.
- Lacivita, Enza,Schepetkin, Igor A.,Stama, Madia L.,Kirpotina, Liliya N.,Colabufo, Nicola A.,Perrone, Roberto,Khlebnikov, Andrei I.,Quinn, Mark T.,Leopoldo, Marcello
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p. 3913 - 3924
(2015/06/22)
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- Discovery of N-methyl-1-(1-phenylcyclohexyl)methanamine, a novel triple serotonin, norepinephrine, and dopamine reuptake inhibitor
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The current work discloses a novel cyclohexylarylamine chemotype with potent inhibition of the serotonin, norepinephrine, and dopamine transporters and potential for treatment of major depressive disorder. Optimized compounds 1 (SERT, NET, DAT, IC50 = 169, 85, 21 nM) and 42 (SERT, NET, DAT IC50 = 34, 295, 90 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 30 mpk po and were not general motor stimulants.
- Shao, Liming,Hewitt, Michael C.,Wang, Fengjiang,Malcolm, Scott C.,Ma, Jianguo,Campbell, John E.,Campbell, Una C.,Engel, Sharon R.,Spicer, Nancy A.,Hardy, Larry W.,Schreiber, Rudy,Spear, Kerry L.,Varney, Mark A.
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p. 1438 - 1441
(2011/04/16)
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- Anti-viral method
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PCT No. PCT/US97/07431 Sec. 371 Date Jan. 6, 1999 Sec. 102(e) Date Jan. 6, 1999 PCT Filed May 2, 1997 PCT Pub. No. WO97/41846 PCT Pub. Date Nov. 13, 1997The present invention provides compounds which inhibit an envelope virus by inhibiting the fusion of the virus with the host cell. The virus may be inhibited in an infected cell, a cell susceptible of infection or a mammal in need thereof.
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- Urea, thiourea and guanidine compounds and their use as anti-viral agents
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The present invention provides compounds which inhibit an envelope virus by inhibiting the fusion of the virus with the host cell. The virus may be inhibited in an infected cell, a cell susceptible of infection or a mammal in need thereof.
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- Inhibitors of Acyl-CoA:Cholesterol Acyltransferase. 4. A Novel Series of Urea ACAT Inhibitors as Potential Hypocholesterolemic Agents
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We have synthesized a series of N-phenyl-N'-aralkyl and N-phenyl-N'-(1-phenylcycloalkyl)ureas as inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT).This intracellular enzyme is thought to be responsible for the esterification of dietary cholesterol; hence inhibition of this enzyme could reduce diet-induced hypercholesterolemia.For this series of compounds, the in vitro ACAT inhibitory activity was improved by increasing the bulk of the 2,6-substituents on the phenyl ring.Additionally, we found that spacing of the aromatic rings was critical for ACAT inhibitory activity.A phenyl ring five atoms away from the requiste 2,6-diisopropylphenyl moiety was optimal for in vitro activity.Substitution α to the N'-phenyl moiety enhanced in vitro potency.In the case of phenylcycloalkyl ureas, ACAT inhibitory activity was independent of the size of the cycloalkyl ring.From this series of analogs, compound 25, which had excellent in vitro potency for inhibiting ACAT, was found to lower plasma cholesterol by 73percent in vivo when administrated in the diet at 50 mg/kg in an animal model of hypercholesterolemia.In this model, compound 25 lowered plasma cholesterol dose dependently and was as efficacious as the Lederle ACAT inhibitor CL 277082.
- Trivedi, Bharat K.,Holmes, Ann,Stoeber, Terri L.,Blankley, C. John,Roark, W. Howard,et al.
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p. 3300 - 3307
(2007/10/02)
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- Synthesis and Anticonvulsant Activity of 1-Phenylcyclohexylamine Analogues
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Thirty-eight analogues of 1-phenylcyclohexylamine (PCA), a phencyclidine (PCP) derivative, were examined for their activities in the mouse maximal electroshock (MES) seizure test and in a motor-toxicity assay.In addition, we determined the binding affinities of the compounds for PCP acceptor sites in rat brain membranes labeled with -1-piperidine.Many of the analogues were protective against MES seizures (ED50s of 4-41 mg/kg, ip) and all of these compounds caused motor toxicity.The potencies in the motor toxicity and MES seizure tests showed a moderate correlation with the affinities for PCP sites.Several analogues exhibited a greater separation of potencies in the motor toxicity and MES seizure tests than did the parent compound PCA.These were obtained by (i) 3-methylation of the cyclohexyl ring trans to the phenyl ring, (ii) methoxylation at the ortho position on the phenyl ring, and (iii) contraction of the cyclohexane ring to form the corresponding cyclopentane.
- Thurkauf, Andrew,Costa, Brian de,Yamaguchi, Shun-ichi,Mattson, Mariena V.,Jacobson, Arthur E.,et al.
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p. 1452 - 1458
(2007/10/02)
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- N6 -substituted adenosines
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The present inventions are novel N6 -substituted adenosines wherein the N substituent is STR1 wherein Ar is an unsubstituted or substituted (1) phenyl, (2) 1- or 2-naphthalenyl, (3) 2- or 3-thienyl, (4) 2- or 3-furanyl, (5) 2-, 4-, or 5-thiazyl, (6) 2-, 3-, or 4-pyridyl, or (7) 2-pyrimidyl wherein the substituents include at least one of lower alkyl, halo, trifluoromethyl, hydroxy, lower alkoxy, lower acyloxyamino, N-lower monoalkyl or N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, or nitro and R' is hydrogen or alkyl, A is STR2 wherein q, q', or q" are one to four, n and m are independently zero to three provided if A is a bond then n and m is at least 2 and if A is other than a bond then n and m is at least one. These novel adenosines have highly desirable central nervous system and cardiovascular activities and therefore the present invention also includes pharmaceutical compositions and methods of use therefor.
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