Overcoming the Drawbacks of Sulpiride by Means of New Crystal Forms

This study aims at developing new multicomponent crystal forms of sulpiride, an antipsychotic drug. The main goal was to improve its solubility since it belongs to class IV of the BCS. Nine new adducts were obtained by combining the active pharmaceutical ingredient with acid coformers: a salt cocrystal and eight molecular salts. In addition, three novel co-drugs, of which two are molecular salts and one is a cocrystal, were also achieved. All samples were characterized in the solid state by complementary techniques (i.e., infrared spectroscopy, powder X-ray diffraction and solid-state NMR). For systems for which it was possible to obtain good-quality single crystals, the structure was solved by single crystal X-ray diffraction (SCXRD). SCXRD combined with solid-state NMR were used to evaluate the ionic or neutral character of the adducts. In vitro dissolution tests of the new crystal forms were performed and all the adducts display remarkable dissolution properties with respect to pure sulpiride

Synthesis and biological evaluation of proline derivatives as potential angiotensin converting enzyme inhibitor.

The synthesis of a series of proline derivatives (1a-e and 2a-b) as pure isomers is described. These compounds were evaluated in vitro for their ability to inhibit angiotensin converting enzyme (ACE) and compared to the potency of captopril taken as a reference drug. They showed only a weak ACE inhibitory activity

Synthesis and biological activity of lipocortin-5 N-terminus: An attempt to define some structural requirements for activity

We have determined that the peptide lipocortin-5 N-terminus (LIPO-5NT) was able to inhibit rabbit platelet aggregation in a concentration- and time-dependent manner. In order to assess which residues in LIPO-5NT were essential for its activity, an 'Ala-scan' was performed by sequentially substituting alanine for each of the first six residues. We demonstrate that replacement of Gln3 by alanine increases inhibition by about 20 times, while substitution of Leu5 gives an increase in activity of about 70 times

Synthesis and biological activity of tripeptide FR113680 analogues containing unconventional amino acids.

In order to further develop structure-ativity relationships and to get information about the biological active conformations we synthetized analogues tuipeptide to the FR 113680 [Ac-Thr-D-Trp(CHO)-)-PheNMeBzl; Ac: acethyl], in which the phenylalanine residue was replaced by unconventional amino acids [1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic); (3aS, 7aS)-octahydroindole-2-carboxylic acid (Oic); (S,S,S)-2-azabiciclo[3.3.0] octane-3-carboxylic acid (Aoc); 3-(1'-naphthyl) alanine (Nap), pheny(glicine (Phg); thienylalanine (Thi)]. The biological activity off he peptides was performed on guinea pig ileum for neurokinin 1 (NK-1) and on rat colon for neurokinin 2 (NK-2). In particular, the replacement of the Phe(3) by the Oic (8(a)) gave an higher antagonist activity in both NK-1 and NK-2 receptors, but no improvement in selectivity with respect to reference tripeptide (FR113680). The compound (8(a)) represent the first example of highly potent peptides that do not contain an aromatic amino acid of the third position as had been previously considered essential

Molecular structures of quinuclidinic neurokinin antagonists: 2-(2-phenylbenzylidene)-3-(2-X-benzylamino) derivatives

The solid-state molecular conformations and crystal structures of three analogues of the CP-96,345 molecule, an important nonpeptidic SP antagonist, namely the (±)-2-(3-phenylbenzilidene)-3-(2-benzylamino) quinuclidine, the o-chloro- and the o-methoxy-derivatives, have been determined by X-ray diffusion analyses and refined to final R values of 0.055, 0.045, and 0.056, respectively. All three molecules in the solid state show the same disposition of the substituents of the double bond and differences in the conformation mainly caused by the need of releasing intramolecular strains and/or nonbonded interactions. The observed molecular structures are compared to the reported solid-state structure of the CP-96,345 and correlated to the biological activity as NK antagonists

Conformational analysis of three NK1 tripeptide antagonists: A proton nuclear magnetic resonance study

Two new peptides, tailored after Ac-Thr-D-Trp(CHO)-Phe-NMeBzl (TRI), namely, Ac-Thr-D-Trp(CHO)-Phe-NMeαMeBzl (TRA) and Ac-Thr-D-Trp(CHO)-Oic- NMeBzl (TOI), in which Phe is replaced by (3aS,7aS)-octahydroindole-2- carboxylic acid, proved more potent and selective NK1 antagonists. The conformational properties of all three compounds were investigated in solution by NMR spectroscopy and those of TRI analyzed in greater detail by means of systematic computer-assisted modeling. All conformers whose energy differs by less than 9 kcal/mol from the absolute minimum are different from the conformer proposed in a previous molecular modeling study by the discoverers of TRI. Parallel calculations for TRA and TOI yield low-energy conformers similar to those of TRI but in a slightly different order. Comparison of the shapes of low-energy conformers of all three peptides with those of four typical rigid NK1 antagonists shows that putative bioactive conformations are indeed present in solution

X-ray Structural Analysis of Ethyl [2,2-dimethyl-6-(D2-thiazolin-2-yl)-4H-1,4-benzoxazin-3-one-4-yl]butyrate.

With the aim of discovering new molecules with K+ channel modulating properties, we have synthesized analogues of cromakalim, an important molecule which shows specific affinity toward the K+ channels, by replacing the benzopyrane ring with a benzoxazine moiety. As a part of this study, we have synthesized and characterized, in solution and in the solid state as well, the compound ethyl [2,2-dimethyl-6-(A2-thiazolin-2-yl)-4H-l,4-benzoxazin-3-one-4-yl]butyrate (V). This compound exhibits in the solid state the following parameters: molecular formula C19H24N2O4S, triclinic, space group PI, Mw = 376.5, a = 12.581(3) A, b = 5.485(4) A, c = 14.612(2) A, a = 91.85(2), 0 = 108.9(3), y = 82.04(4), V = 944.7 A3, Z = 2, d = 1.323 g-cnT3. We describe here the synthesis and discuss the solid-state conformation of this new molecule; when tested on rat aorta ring precontracted with phenylephrine, the compound showed a concentrationdependent relaxation comparable to that measured for cromakalin taken as reference drug

Synthesis and in vitro activities of NK-1 antagonists derived from L-Triptophan.

A study of structure-activity relationships of a series of L-tryptophan derivative NK-1 antagonist was performed using 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-Tryptophan (IV) as a starting point. The ester moiety was replaced with several amidic functions while the N-acetyl group (Ac-) was retained (compounds 1-8) or changed into a benzyloxycarbonyl group (Z-) (compounds 9-16). The compounds were tested on guinea pig ileum longitudinal muscle, rat colon muscolaris mucosae, and rat everted portal vein, representative of tachykinin NK-1, NK-2 and NK-3 receptors, respectively. Both, Ac- and Z-series showed generally moderate antagonist activity on tachykinin NK-1 receptors with respect to the reference drug IV. The most potent term was compound 2 (Ac-Trp-N(CH3)CH(CH3)Ph with S-configuration at the C-terminus) which exhibited pA2 values of 7.0, 4.2 and 4.4 on NK-1, NK-2 and NK-3 sites, respectively

Synthesis of new 1,2,3-benzotriazin-4-one-arylpiperazine derivatives as 5-HT1A serotonin receptor ligands.

A series of novel 1,2,3-benzotriazin-4-ones I (R = H, Cl, MeO, F, 3-CF3O; n = 2, 3) were prepd. and evaluated as ligands for 5-HT receptors. Radioligand binding assays proved that the majority of I behaved as good to excellent ligands at the 5-HT1A receptor, some of which were selective with respect 5-HT2A and 5-HT2C receptors. Six analogs were selected and further evaluated for their binding affinities on D1, D2 dopaminergic, and a1-, a2-adrenergic receptors. I (R = 2-MeO, n = 3) bound at 5-HT1A sites with subnanomolar affinity and showed high selectivity over all considered receptors and may offer a new lead for the development of therapeutically efficacious agents