- Harnessing the anti-nociceptive potential of nk2 and nk3 ligands in the design of new multifunctional μ/δ-opioid agonist–neurokinin antagonist peptidomimetics
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Opioid agonists are well-established analgesics, widely prescribed for acute but also chronic pain. However, their efficiency comes with the price of drastically impacting side effects that are inherently linked to their prolonged use. To answer these liabilities, designed multiple ligands (DMLs) offer a promising strategy by co-targeting opioid and non-opioid signaling pathways involved in nociception. Despite being intimately linked to the Substance P (SP)/neurokinin 1 (NK1) system, which is broadly examined for pain treatment, the neurokinin receptors NK2 and NK3 have so far been neglected in such DMLs. Herein, a series of newly designed opioid agonist-NK2 or-NK3 antagonists is reported. A selection of reported peptidic, pseudo-peptidic, and non-peptide neurokinin NK2 and NK3 ligands were covalently linked to the peptidic μ-opioid selective pharma-cophore Dmt-DALDA (H-Dmt-D-Arg-Phe-Lys-NH2 ) and the dual μ/δ opioid agonist H-Dmt-D-Arg-Aba-βAla-NH2 (KGOP01). Opioid binding assays unequivocally demonstrated that only hybrids SBL-OPNK-5, SBL-OPNK-7 and SBL-OPNK-9, bearing the KGOP01 scaffold, conserved nanomo-lar range μ-opioid receptor (MOR) affinity, and slightly reduced affinity for the δ-opioid receptor (DOR). Moreover, NK binding experiments proved that compounds SBL-OPNK-5, SBL-OPNK-7, and SBL-OPNK-9 exhibited (sub)nanomolar binding affinity for NK2 and NK3, opening promising opportunities for the design of next-generation opioid hybrids.
- Ballet, Steven,Gadais, Charlène,Janecka, Anna,Martin, Charlotte,Neve, Jolien De,Piekielna-Ciesielska, Justyna
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supporting information
(2021/09/13)
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- SUBSTITUTED ALKYNYLENE COMPOUNDS AS ANTICANCER AGENTS
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The present invention relates to substituted alkynylene compounds represented by compound of formula (I) pharmaceutically acceptable salts and stereoisomers thereof. The present invention further provides the methods of preparation of compound of formula (I) and therapeutic uses thereof as anti-cancer agents.
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Page/Page column 48
(2019/08/08)
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- NOVEL SUBSTITUTED AMIDES OF TRITERPENE DERIVATIVES AS HIV INHIBITORS
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The present invention relates to compounds of novel substituted amides of triteripene derivatives of formula (I); or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, tautomers, stereoisomers, prodrugs, compositions or combination thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, X, Y, Z1, Z2, Z3 and formula (II) are as defined herein. The present invention also relates to,, and pharmaceutical compositions comprising compounds of formula (I) useful for the treatment of viral diseases and particularly HIV mediated diseases.
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Page/Page column 29
(2017/02/28)
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- C-3 NOVEL TRITERPENONE WITH C-28 REVERSE AMIDE DERIVATIVES AS HIV INHIBITORS
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Formula (I) The invention relates to C-3 novel triterpenone with C-28 reverse amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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Page/Page column 55; 56
(2016/11/21)
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- New cathepsin inhibitors to explore the fluorophilic properties of the S2 pocket of cathepsin B: Design, synthesis, and biological evaluation
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Fluor-in or out? Based on β,β-difluorinated cycloaliphatic amino acids, a library of new dipeptide nitriles was evaluated as human cathepsin inhibitors. The orientation of the fluorinated face relative to the protein structure of cathepsin B was elucidated by molecular modeling and NMR studies (see figure). For (R)-configured eutomers, the fluorine atoms are directed to the S2 pocket, whereas in (S)-configured distomers, the fluorinated face is solvent-exposed.
- Fustero, Santos,Rodrigo, Vanessa,Sanchez-Rosello, Maria,Del Pozo, Carlos,Timoneda, Joaquin,Frizler, Maxim,Sisay, Mihiret T.,Bajorath, Juergen,Calle, Luis P.,Canada, F. Javier,Jimenez-Barbero, Jesas,Guetschow, Michael
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supporting information; scheme or table
p. 5256 - 5260
(2011/06/24)
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- Collection of traceable compounds and uses thereof
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The use of a collection of compounds of general formula (I), wherein: n is 0 or 1; p represents an integer between 1 and 6; r represents an integer between 1 and 12; R1 and R′1 represent in particular a hydrogen atom; R2 represents an amino acid side chain or an amino acid derivative; R3 represents a group derived from a carboxylic acid, bearing a basic entity; R4 represents in particular an alkyl group containing 1 to 10 carbon atoms; and A represents a hydrogen atom, a protecting group or a tracing group, in particular a fluorophor, a coloring agent or a quencher, for determining, through binding studies, ligands of receptors whose ligand is unknown or whose ligand useful for carrying out specific affinity binding assays is unknown.
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- Imidazol-4-one and Imidazole-4-thione Compounds
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Imidazol-4-one or imidazole-4-thione compounds of formula (I): wherein X, R1, R2, R3, R4, R5, and R6 are defined herein. Also disclosed is a method for treating a cannabinoid receptor-mediated disorder with these compounds.
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Page/Page column 16-17
(2010/05/13)
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- 1,3-Dihydro-2H-Indole-2-One Compound and Pyrrolidine-2-One Compound Fused With Aromatic Heterocycle
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It is intended to provide a drug which is efficacious against pathological conditions relating to arginine-vasopressin V1b receptor. More particularly speaking, it is intended to provide a drug which has a therapeutic or preventive effect on depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, hypertension, digestive diseases, drug addiction, epilepsy, brain infarction, brain ischemia, brain edema, head injury, inflammation, immune diseases, alopecia and so on. As the results of intensive studies, a novel 1,3-dihydro-2H-indol-2-one compound and a pyrrolidin-2-one compound fused with a heteroaromatic ring, which are highly selective antagonists of arginine-vasopressin V1b receptor, have high metabolic stabilities and show favorable brain penetration and high plasma concentrations, are found, thereby achieving the above objective.
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Page/Page column 89
(2009/01/24)
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- PEPTIDIC COMPOUNDS
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The present invention provides a compound of formula (I), (II), (III) and (IV) as defined herein and pharmaceutically acceptable derivatives thereof. The present invention further provides use of the compounds of the present invention in the treatment of bacterial infection and in the treatment of HIV infection. Also provided are pharmaceutical compositions comprising the compounds of the present invention.
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Page/Page column 81
(2008/06/13)
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- AMIDOPYRAZOLE DERIVATIVE
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A platelet coagulation inhibitor which inhibits neither COX-1 nor COX-2 is provided. The inhibitor is a compound represented by general formula (I): wherein Ar1 and Ar2 independently represent a 5- or 6-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents, or a phenyl group optionally substituted with 1 to 3 substituents; R1 represents a lower acyl group, carboxyl group, a lower alkoxycarbonyl group, a lower alkoxy group, a lower alkyl group optionally substituted with 1 or 2 substituents, a carbamoyl group optionally substituted with 1 or 2 substituents, an oxamoyl group optionally substituted with 1 or 2 substituents, an amino group optionally substituted with 1 or 2 substituents, a 4- to 7-membered alicyclic heterocyclic group optionally substituted with 1 or 2 substituents, a phenyl group optionally substituted with 1 to 3 substituents, or a 5- or 6-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents; and R2 represents hydrogen atom, a halogeno group, or the like.
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Page/Page column 42
(2010/11/23)
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- GLYT2 MODULATORS
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α-, β-, and γ-amino acid derivatives of formula I are disclosed as selective GlyT2 inhibitors for the treatment of central nervous system (CNS) conditions such as muscle spasticity, tinnitus, epilepsy and neuropathic pain. Formula I
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Page/Page column 105
(2010/02/11)
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- HYDROXY PYRIDOPYRROLOPYRAZINE DIONE COMPOUNDS USEFUL AS HIV INTEGRASE INHIBITORS
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Hydroxy-substituted pyridopyrrolopyrazine dione compounds are inhibitors of HIV integrase and inhibitors of HIV replication. In one embodiment, the dione compounds are of Formula (I): (I) wherein a, b, A, B, R1, R2, R3, R4, R5, R6, R7 and R8 are defined herein. The compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.
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Page/Page column 103
(2010/02/11)
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- Novel glycine transporter type-2 reuptake inhibitors. Part 1: α-amino acid derivatives
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A variety of α-amino acid derivatives were prepared as glycine transport inhibitors and their ability to block the uptake of [ 14C]-glycine in COS7 cells transfected with human glycine transporter-2 (hGlyT-2) was evaluated. An array of substituents at the chiral center was studied and overall, L-phenylalanine was identified as the preferred amino acid residue. Compounds prepared from L-amino acids were more potent GlyT-2 inhibitors than analogs derived from the corresponding D-amino acids. Introducing an achiral amino acid such as glycine, or incorporating geminal substitution in the α-position, led to a significant reduction in GlyT-2 inhibitory properties.
- Wolin, Ronald L.,Venkatesan, Hariharan,Tang, Liu,Santillán Jr., Alejandro,Barclay, Tristin,Wilson, Sandy,Lee, Doo Hyun,Lovenberg, Timothy W.
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p. 4477 - 4492
(2007/10/03)
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- ARYLGLYCINE DERIVATIVES FOR USE AS GLYCINE TRANSPORT INHIBITORS
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The present invention relates to compounds of Formula (I) and salts solvates and hydrates thereof. The invention further relates to pharmaceutical compositions containing said compounds and methods of treating neurological and neuropsychistric disorders using said compounds.
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- Certain thiol inhibitors of endothelin-converting enzyme
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Disclosed as endothelin converting enzyme inhibitors are the compounds of the formula wherein the variables have the meanings as defined hereinbefore.
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- Synthesis and structure-activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores
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Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(α-methylbenzyl)-2-piperidinecarboxamide (2) as structural leads, a variety of analogues were synthesised and evaluated for anticonvulsant activity in the MES test in mice. In the N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl2, or 3-CF3 groups on the aromatic ring led to an increase in MES activity. Replacement of the α-methyl group by either i-Pr or benzyl groups enhanced MES activity with no increase in neurotoxicity. Substitution on the piperidine ring nitrogen led to a decrease in MES activity and neurotoxicity, while reduction of the amide carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the piperidine ring decreased MES activity and neurotoxicity. Incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrinone nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, opening of the piperidine ring between the 1- and 6-positions gave the active norleucine derivative 75 (ED50 = 5.8 mg kg-1, TD50 = 36.4 mg kg-1, PI = 6.3). Replacement of the piperidine ring of 1 by cycloalkane (cyclohexane, cyclopentane, and cyclobutane) resulted in compounds with decreased MES activity and neurotoxicity, whereas replacement of the piperidine ring by a 4-pyridyl group led to a retention of MES activity with a comparable PI. Simplification of the 2-piperidinecarboxamide nucleus of 1 into a glycinecarboxamide nucleus led to about a six-fold decrease in MES activity. The 2,6-dimethylanilides were the most potent compounds in the MES test in each group of compounds evaluated, and compounds 50 and 75 should be useful leads in the development of agents for the treatment of tonic-clonic and partial seizures in man.
- Ho, Bin,Michael Crider,Stables, James P
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p. 265 - 286
(2007/10/03)
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- Dipeptides which promote release of growth hormone
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Compounds of formula (I) are growth hormone releasing peptide mimetics which are useful for the treatment and prevention of osteoporosis. STR1
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- Efficient large scale preparation of neutral endopeptidase/ angiotensin-converting enzyme dual inhibitor CGS30440
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The development and piloting of a potential manufacturing process for ACE/NEP dual inhibitor CGS30440 is described. The synthesis proceeds sequentially from 1-aminocyclopentanecarboxylic acid via N-protection, peptide coupling with L-tyrosine ethyl ester, O-methylation of N-protected [(1-amino-1-cyclopentyl)carbonyl]-L-tyrosine ethyl ester, N-deprotection, peptide coupling of [(1-amino-1-cyclopentyl)carbonyl]-O-methyl-L-tyrosine ethyl ester with D-2-bromo-3-methylbutyric acid, and final displacement of bromide with thioacetate. This approach is superior to shorter Discovery routes based upon final peptide coupling of L-2-(acetylthio)-3-methylbutanoic acid to [(1-amino-1-cyclopentyl)carbonyl]-O-methyl-L-tyrosine ethyl ester.
- Johnson, Erik P.,Cantrell Jr., William R.,Jenson, Todd M.,Miller, Scott A.,Parker, David J.,Reel, Noela M.,Sylvester, Leo G.,Szendroi, Robert J.,Vargas, Kevin J.,Xu, Jean,Carlson, John A.
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p. 238 - 244
(2013/09/08)
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- An efficient and high yield method for the N-tert-butoxycarbonyl protection of sterically hindered amino acids
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An important method for the N-tert-butoxycarbonyl protection of the amino functionality of α-alkylated prolines and other sterically hindered α,α-disubstituted amino acids has been developed in which the lipophilic base tetramethylammonium hydroxide is used to solubilize the otherwise insoluble zwitterionic amino acid in acetonitrile, thereby obviating the need for an aqueous medium.
- Khalil, Ehab M.,Subasinghe, Nalin L.,Johnson, Rodney L.
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p. 3441 - 3444
(2007/10/03)
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- CYCLIC AMINO ACID DERIVATIVES
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Disclosed are the compounds of formula I STR1 wherein R represents hydrogen, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl or cycloalkyl-lower alkyl; R 1 represents hydrogen, lower alkyl, cycloalkyl, carbocyclic aryl or heterocyclic aryl, or biaryl; R 3 represents hydrogen or acyl; R 4 represents hydrogen, lower alkyl, carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aryl-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, biaryl or biaryl-lower alkyl; R 5 represents hydrogen or lower alkyl; or R 4 and R 5 together with the carbon atom to which they are attached represent cycloalkylidene or benzo-fused cycloalkylidene; A together with the carbon atom to which it is attached represents 3 to 10 membered cycloalkylidene or 5 to 10 membered cycloalkenylidene radical which may be substituted by lower alkyl or aryl-lower alkyl or may be fused to a saturated or unsaturated carbocyclic 5-7-membered ring; or A together with the carbon to which it is attached represents 5 or 6 membered oxacycloalkylidene, thiacycloalkylidene or azacycloalkylidene optionally substituted by lower alkyl or aryl-lower alkyl; or A together with the carbon atom to which it is attached represents 2,2-norbornylidene; m is 0, 1, 2 or 3; and COOR 2 represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester, disulfide derivatives derived from said compounds wherein R 3 is hydrogen; and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising said compounds; methods for preparation of said compounds; intermediates; and methods of treating disorders in mammals which are responsive to ACE and NEP inhibition by administration of said compounds to mammals in need of such treatment.
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- CYCLIC AMINO ACID DERIVATIVES
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Disclosed are the compounds of formula I STR1 wherein R represents hydrogen, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl or cycloalkyl-lower alkyl;R 1 represents hydrogen, lower alkyl, cycloalkyl, carbocyclic aryl or heterocyclic aryl, or biaryl; R 3 represents hydrogen or acyl; R. sub.4 represents hydrogen, lower alkyl, carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aryl-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, biaryl or biaryl-lower alkyl;R 5 represents hydrogen or lower alkyl;A together with the carbon atom to which it is attached represents 3 to 10 membered cycloalkylidene or 5 to 10 membered cycloalkenylidene radical which may be substituted by lower alkyl or aryl-lower alkyl or may be fused to a saturated or unsaturated carbocyclic 5-7-membered ring; or A together with the carbon to which it is attached represents 5 or 6 membered oxacycloalkylidene, thiacycloalkylidene or azacycloalkylidene optionally substituted by lower alkyl or aryl-lower alkyl;m is 0, 1, 2 or 3; andCOOR 2 represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester;disulfide derivatives of said compounds wherein R 3 is hydrogen; and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising said compounds; methods for preparation of said compounds; intermediates; and methods of treating disorders in mammals which are responsive to ACE and NEP inhibition by administration of said compounds to mammals in need of such treatment.
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- Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides
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Antiinflammatory and analgesic oxindole prodrugs of the formula STR1 wherein R10, R11, R12 and R13 are hydrogen, alkyl or halogen and R is methyleneoxyalkanoyl, methyleneoxyalkenoyl or alkenoyl.
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