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Nervous System Diseases

Digestive System Disorders

Small molecule drug

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Nervous System Diseases	1

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Small molecule drug	1

A series of N-[biphenylyl(tetrazolyl)methyl]-2-butylimidazoles containing variously substituted diazine or pyridine moieties either as their free bases or N-oxide derivatives attached to the 4-position of the imidazole ring was synthesized and tested for interaction with the AT1 receptors of rat adrenal cortex membranes (receptor binding assay). Some compounds were then chosen for further evaluation in vivo in the A II-induced pressor response in conscious normotensive rats. The most potent in the AT1 binding assay were found to be compounds in which the diazine or pyridine ring nitrogen is adjacent to the point of attachment between the two heteroaromatic rings such as 2-butyl-4-(3,6-dimethylpyrazin-2-yl)-1-[[2'-(1H-tetrazol-5-y l)-biphenyl-4- yl]methyl]-1H-imidazole (3b) or 2-butyl-4-[5-(methoxycarbonyl)pyrid-2-yl]-1-[[2'-(1H-tetrazol++ +-5- yl)biphenyl-4-yl]methyl]-1H-imidazole (6c). The binding affinities and oral activities of the pyridine N-oxide imidazoles in which a stabilizing group ortho to the pyridine ring nitrogen is present were markedly improved as in 2-butyl-4-[(3-methoxycarbonyl)-6-methyl-N-oxopyridin-2-yl]-1-[[2'- (1H- tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole 31b. Molecular modeling studies were carried out to determine the molecular electrostatic potential values of related model systems and to correlate their receptor interaction energies with the observed activities of our compounds.

01 Jan 1995·Journal of the Chemical Society, Perkin Transactions 2

Structure and conformation of (1S,2R)-cis-2-[hydroxyaminocarbonylmethyl(N-methyl)aminocarbonyl]cyclohexanecarboxylic acid: X-ray, NMR and molecular mechanics studies

Author: Dapporto, Paolo ; Paoli, Paola ; Di Bugno, Cristina ; Giorgi, Raffaello ; Colombani, Spartaco Mauro

The structural characterization of idrapril, (1S,2R)-cis-2-[hydroxyaminocarbonylmethyl(N-methyl)-aminocarbonyl]cyclohexanecarboxylic acid (I), a novel ACE inhibitor and its related benzyloxy derivative (II) has been carried out by NMR studies.The crystal structure of II has been determined by x-ray diffraction.The NMR spectra indicate the presence of two cis and trans isomers with respect to the amide bond at room temperature, with rotational barriers of 70 kJ mol^-1.The preferred conformation of these compounds is the trans rotamer with the carboxylic moiety in the equatorial orientation.Conformational studies in aqueous solution have been reported for idrapril as a function of pH and the equilibrium constant has been determinedThe results suggest the presence of intramol. hydrogen bonds, as is confirmed by mol. mechanics calculations

01 Mar 1993·Journal of Medicinal ChemistryQ1 · MEDICINE

1,2-Cyclomethylencarboxylic monoamide hydroxamic derivatives. A novel class of non-amino acid angiotensin converting enzyme inhibitors

Q1 · MEDICINE

Article

Author: Garzelli, Giorgio ; Di Bugno, Cristina ; Criscuoli, Marco ; Cerbai, Guido ; Subissi, Alessandro ; Giorgi, Raffaello ; DePriest, Scott A. ; Turbanti, Luigi ; Renzetti, Anna R. ; Bramanti, Giancarlo

A series of monoamidic derivatives of cis- and trans-1,2-cyclohexanedicarboxylic and 1,2-cyclopentanedicarboxylic acids bearing either a carboxylic, sulfhydrylic, or hydroxamic group in the side chain were synthesized and evaluated in vitro for their inhibitory activity against angiotensin converting enzyme. The compounds were designed as potential ACE inhibitors of novel structure, assuming that a monoamidic residue of an 1,2-cyclomethylenedicarboxylic acid could be an alternative structure to the acylproline moiety, the carboxyl-terminal portion common to various ACE inhibitors. The most active compounds were found in the hydroxamic derivatives of cyclohexane series; within this series of derivatives a marked increase of potency was caused by alkylation of the amidic nitrogen with a methyl or ethyl group. Therefore enantiomers of the selected hydroxamic derivatives of cis- and trans-1,2-cyclohexanedicarboxylic acid were prepared by two different chiral synthetic routes and evaluated in vitro for their ACE inhibitor potencies. The active enantiomers both of the cis series (21a, 21c) and trans series (16b, 16d) were found to have all R configuration at the C-2 and R or S configuration at the C-1, while in the classical ACE inhibitors S configuration at the terminal carboxylate (corresponding to the C-1 of our compounds) is strictly required for activity. The most potent compound of the series was (1S,2R)-cis-2[[[2-(hydroxyamino)-2-oxoethyl]methylamino]carbonyl] cyclohexanecarboxylic acid (21a) with an IC50 value of 7.0 nM compared with the value of 3.0 nM for captopril. Further 21a was shown to be highly selective and competitive ACE inhibitor. These results indicate that this non-amino acid structure of inhibitors meets the ACE active site requirements for the binding. The binding compatibility of the most active compounds with a model of ACE active site was evaluated by molecular modeling techniques.

100 Deals associated with Laboratori Guidotti SpA

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100 Translational Medicine associated with Laboratori Guidotti SpA

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Pipeline

Pipeline Snapshot as of 14 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

Rociverine	Spasm biliary More	Approved
Idrapril ( ACE )	Hypertension More	Discontinued
Mequitamium iodide ( H1 receptor x mAChRs )	Asthma More	Discontinued
LG-50643 ( mAChRs )	Asthma More	Pending