- New anthranilic acid based antagonists with high affinity and selectivity for the human cholecystokinin receptor 1 (hCCK1-R)
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The anthranilic acid diamides represent the most recent class of nonpeptide CCK1 receptor (CCK1-R) antagonists. Herein we describe the second phase of the anthranilic acid C-terminal optimization using nonproteinogenic amino acids containing a phenyl ring in their side chain. The Homo-Phe derivative 2 (VL-0797) enhanced 12-fold the affinity for the rat CCK1-R affinity and 15-fold for the human CCK1-R relative to the reference compound 12 (VL-0395). The eutomer of 2 (6) exhibited a nanomolar range affinity toward the human CCK1-R and was at least 400-fold selective for the CCK1-R over the CCK2-R. Molecular docking in the modeled CCK1-R and its validation by site-directed mutagenesis experiments showed that the 6 binding site overlaps that occupied by the C-terminal bioactive region of the natural agonist CCK. Owing to their interesting properties, new compounds provided by this study represent a solid basis for further advances aimed at synthesis of clinically valuable CCK1-R antagonists.
- Pavan, Michela V.,Lassiani, Lucia,Berti, Federico,Stefancich, Giorgio,Ciogli, Alessia,Gasparrini, Francesco,Mennuni, Laura,Ferrari, Flora,Escrieut, Chantal,Marco, Esther,Makovec, Francesco,Fourmy, Daniel,Varnavas, Antonio
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experimental part
p. 5769 - 5785
(2011/10/09)
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- Structure activity studies of the serine-AIB dipeptide domain in 2,3-dihydroisothiazole based growth hormone secretagogues
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A series of growth hormone secretagogues (GHSs) based on 2,3-dihydroisothiazole has been synthesized in the search for a potential treatment of growth hormone deficiency or frailty in the elderly. This paper describes the evaluation of the SAR of the benzyl-d-Ser-aminoisobutyric acid dipeptide fragment. Introduction of substituents in the peptide backbone and in the phenyl ring has been investigated, as well as replacements for the benzyl group and for the AIB residue. A number of modifications resulted in enhanced potency over the parent benzyl-d-Ser-AIB derivative.
- Evers, Britta,Ruehter, Gerd,Berg, Martina,Dodge, Jeffrey A.,Hankotius, Dirk,Hary, Ulrike,Jungheim, Louis N.,Mest, Hans-Juergen,De La Nava, Eva-Maria Martin,Mohr, Michael,Muehl, Brian S.,Petersen, Soenke,Sommer, Birgit,Riedel-Herold, Grit,Tebbe, Mark J.,Thrasher, Kenneth J.,Voelkers, Silke
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p. 6748 - 6762
(2007/10/03)
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- Growth hormone secretagogues
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What is disclosed are growth hormone secretagogues, and their uses, of the formula wherein R1 is C6H5CH2OCH2—, C6H5(CH2)3— or indol-3-ylmethyl; Y is pyrrolidin-1-yl, 4-C1-C6alkylpiperidin-1-yl or NR2R2; R2 are each independently a C1to C6alkyl; R3 is 2-napthyl or phenyl para-substituted by W; W is H, F, CF3, C1-C6alkoxy or phenyl; and R4 is H or CH3, or a pharmaceutically acceptable salt or solvate thereof.
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Page column 25
(2010/02/09)
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- STEREOSELECTIVE PROCESS FOR THE SYNTHESIS OF (D)-2-AMINO-5-PHENYLPENTANOIC OR ALKYL ESTER THEREOF
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The present invention provides a process for preparing a compound of formula (I); wherein R is a C1-C6 alkyl; or a salt thereof; comprising:(c) hydrolyzing (D,L)-N-acetyl-2-amino-5-phenylpentanoic acid with a suitable base in the pre
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Page/Page column 8-9
(2010/02/07)
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- 2-amino-1,3-propanediol compound and immunosuppressant
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2-Amino-1,3-propanediol compounds of the formula (I) STR1 wherein R is an optionally substituted straight- or branched carbon chain, an optionally substituted aryl, an optionally substituted cycloalkyl or the like, and R2, R3, R4 and R5 are the same or different and each is a hydrogen, an alkyl, an aralkyl, an acyl or an alkoxycarbonyl, pharmaceutically acceptable salts thereof and immunosuppressants comprising these compounds as active ingredients. The 2-amino-1,3-propanediol compounds of the present invention show immunosuppressive action and are useful for suppressing rejection in organ or bone marrow tranplantation, prevention and treatment of autoimmune diseases or as reagents for use in medicinal and pharmaceutical fields.
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