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1.
ACS Med Chem Lett ; 1(8): 411-5, 2010 Nov 11.
Article in English | MEDLINE | ID: mdl-24900225

ABSTRACT

Histone deacetylases are promising molecular targets for the development of antitumor agents. A novel series of histone deacetylase inhibitors of the hydroxamic acid type were synthesized for structure-activity studies. Thirteen tricyclic dibenzo-diazepine, -oxazepine, and -thiazepine analogues were studied and shown to induce variable degrees of histone H3/H4 and tubulin acetylation in a cellular model of myeloid leukemia sensitive to all-trans retinoic acid (ATRA). Multiparametric correlations between acetylation of the three substrates, tumor cell growth inhibition, and ATRA-dependent cytodifferentiation were performed, providing information on the chemical functionalities governing these activities. For two analogues, antitumor activity in the animal was demonstrated.

2.
ChemMedChem ; 5(1): 65-78, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19957262

ABSTRACT

Herein we describe the synthesis of a series of new potent tachykinin NK(2) receptor antagonists by the modulation of the C- and N-terminal moieties of ibodutant (MEN 15596, 1). The N-terminal benzo[b]thiophene ring was replaced by different substituted naphthalenes and benzofurans, while further modifications were evaluated at the C-terminal tetrahydropyran moiety. Most compounds demonstrated a high affinity for the human NK(2) receptor and high in vitro antagonist potency, indicating that a wide range of substituents at both termini can be incorporated in the molecule without detrimental effects on the interactions with the NK(2) receptor. Selected compounds were tested in vivo confirming their activity as NK(2) antagonists. In particular, after both iv and id administration to guinea pig, compound 61 b was able to antagonize NK(2)-induced colonic contractions with a potency and duration-of-action fully comparable to the reference compound 1 (MEN 15596, ibodutant).


Subject(s)
Dipeptides/chemistry , Receptors, Neurokinin-2/antagonists & inhibitors , Thiophenes/chemistry , Animals , Dipeptides/chemical synthesis , Dipeptides/pharmacology , Drug Design , Guinea Pigs , Humans , Receptors, Neurokinin-2/metabolism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/pharmacology
3.
J Med Chem ; 50(3): 550-65, 2007 Feb 08.
Article in English | MEDLINE | ID: mdl-17266207

ABSTRACT

Recently we reported on the design and synthesis of a novel class of selective nonpeptide bradykinin (BK) B2 receptor antagonists (J. Med. Chem. 2006, 3602-3613). This work led to the discovery of MEN 15442, an antagonist with subnanomolar affinity for the human B2 receptor (hB2R), which also displayed significant and prolonged activity in vivo (for up to 210 min) against BK-induced bronchoconstriction in the guinea-pig at a dose of 300 nmol/kg (it), while demonstrating only a slight effect on BK-induced hypotension. Here we describe the further optimization of this series of compounds aimed at maximizing the effect on bronchoconstriction and minimizing the effect on hypotension, with a view to developing topically delivered drugs for airway diseases. The work led to the discovery of MEN 16132, a compound which, after intratracheal or aerosol administration, inhibited, in a dose-dependent manner, BK-induced bronchoconstricton in the airways, while showing minimal systemic activity. This compound was selected as a preclinical candidate for the topical treatment of airway diseases involving kinin B2 receptor stimulation.


Subject(s)
Bradykinin B2 Receptor Antagonists , Bronchodilator Agents/chemical synthesis , Ornithine/analogs & derivatives , Sulfonamides/chemical synthesis , Animals , Blood Pressure/drug effects , Bronchoconstriction/drug effects , Bronchodilator Agents/chemistry , Bronchodilator Agents/pharmacology , CHO Cells , Cricetinae , Cricetulus , Drug Design , Guinea Pigs , Humans , Ileum/drug effects , Ileum/physiology , In Vitro Techniques , Inositol Phosphates/biosynthesis , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Ornithine/chemical synthesis , Ornithine/chemistry , Ornithine/pharmacology , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology
4.
J Med Chem ; 49(12): 3602-13, 2006 Jun 15.
Article in English | MEDLINE | ID: mdl-16759102

ABSTRACT

We recently published the extensive in vivo pharmacological characterization of MEN 16132 (J. Pharmacol. Exp. Ther. 2005, 616-623; Eur. J. Pharmacol. 2005, 528, 7), a member of the sulfonamide-containing human B(2) receptor (hB(2)R) antagonists. Here we report, in detail, how this family of compounds was designed, synthesized, and optimized to provide a group of products with subnanomolar affinity for the hB(2)R and high in vivo potency after topical administration to the respiratory tract. The series was designed on the basis of indications from the X-ray structures of the key structural motifs A and B present in known antagonists and is characterized by the presence of an alpha,alpha-dialkyl amino acid. The first lead (17) of the series was submitted to extensive chemical work to elucidate the structural requirements to increase hB(2) receptor affinity and antagonist potency in bioassays expressing the human B(2) receptor (hB(2)R). The following structural features were selected: a 2,4-dimethylquinoline moiety and a piperazine linker acylated with a basic amino acid. The representative lead compound 68 inhibited the specific binding of [(3)H]BK to hB(2)R with a pKi of 9.4 and antagonized the BK-induced inositolphosphate (IP) accumulation in recombinant cell systems expressing the hB(2)R with a pA(2) of 9.1. Moreover, compound 68 when administered (300 nmol/kg) intratracheally in the anesthetized guinea pig, was able to significantly inhibit BK-induced bronchoconstriction for up to 120 min after its administration, while having a lower and shorter lasting effect on hypotension.


Subject(s)
Bradykinin B2 Receptor Antagonists , Quinolines/chemical synthesis , Sarcosine/analogs & derivatives , Sulfonamides/chemical synthesis , Animals , Bradykinin/metabolism , Bronchoconstrictor Agents/chemical synthesis , Bronchoconstrictor Agents/chemistry , Bronchoconstrictor Agents/pharmacology , CHO Cells , Cricetinae , Cricetulus , Crystallography, X-Ray , Drug Design , Guinea Pigs , Humans , Hypotension/chemically induced , Inositol Phosphates/biosynthesis , Models, Molecular , Molecular Structure , Piperazine , Piperazines/chemistry , Quinolines/chemistry , Quinolines/pharmacology , Radioligand Assay , Receptor, Bradykinin B2/metabolism , Sarcosine/chemical synthesis , Sarcosine/chemistry , Sarcosine/pharmacology , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology
5.
Chemistry ; 10(3): 785-90, 2004 Feb 06.
Article in English | MEDLINE | ID: mdl-14767944

ABSTRACT

Starting from pyrrole- and indole-2-carboxylic acids 5 a and 5 b, the tri- and tetracyclic N,N-dibenzylcyclopropylamines 7 a and 7 b have been synthesized in 52 and 33 % overall yield, respectively. The synthesis of the enantiopure tetracyclic diamine 10 has been achieved applying the established set of reactions to N-tert-butoxycarbonylindoline-2-carboxylic acid (8) in 46 % overall yield. The amide 15 could not be prepared in the same way starting from the N-tert-butoxycarbonylproline 11. In fact, in the allylation step the stereogenic center was deprotonated and the doubly alkylated amide 13 was formed. However, the desired intermediate 15 could be obtained from L-proline in 49 % yield performing first the N-allylation step, then the introduction of the amide function. From 15, the cyclopropane-annelated pyrrolizidine 16 was obtained in 70 % yield as a mixture of (1aS,6aS,6bR)-16 and (1aR,6aS,6bS)-16 diastereoisomers in a ratio of 1:2.9.


Subject(s)
Amides/chemical synthesis , Amino Acids/chemistry , Cyclopropanes/chemistry , Heterocyclic Compounds/chemical synthesis , Titanium/chemistry , Catalysis , Cyclization , Indolizines/chemical synthesis , Molecular Structure , Pyrrolidines/chemical synthesis
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