Luca Francesco Raveglia

Identification of an orally efficacious matrix metalloprotease 12 inhibitor for potential treatment of asthma.

MMP-12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been observed in the lungs of asthmatic patients. Compound 27 was identified as a potent and selective MMP-12 inhibitor possessing good physicochemical properties. In pharmacological studies, the compound was orally efficacious in an MMP-12 induced ear-swelling inflammation model in the mouse with a good dose response. This compound also exhibited oral efficacy in a naturally Ascaris-sensitized sheep asthma model showing significant inhibition of the late phase response to allergen challenge. This compound has been considered for further development as a treatment therapy for asthma.

Recent advances in neurokinin-3 receptor antagonists

This review addresses the recent highlights and progress made in the neurokinin-3 (NK-3) receptor area since the last update, provided in this journal in 1997. Whereas in the neurokinin-1 (NK-1) and neurokinin-2 (NK-2) biological areas literature information based on clinical data account for a high therapeutic potential (in emesis and depression for NK-1 and asthma for NK-2 receptor antagonists), there is a total deficiency of information from NK-3 receptor antagonists in clinical development. No other chemical classes in addition to dichlorophenylalkylpiperidines, represented by SR 142,801 and quinolines, represented by SB-222200 and SB-223412, have been identified by pharmaceutical companies and scientists involved in the specific field. Biological evidence indicates pain/inflammation as a suitable CNS-related therapeutic target, this conclusion is based on localisation studies and efficacy of selected NK-3 receptor antagonists in rat disease models of inflammatory pain. In the periphery, the most likely therapeutic indications might be pulmonary and gastrointestinal tract diseases. It is clearly still premature to anticipate any therapeutic potential in man.

Pharmacological profiles of selective non-peptidic δ opioid receptor ligands

Abstract Several non-peptidic opioids have been synthesized recently as part of a program to develop selective δ receptor agonists. In this study, the affinities of a set of compounds for cloned δ and μ opioid receptors expressed in HEK 293 cell lines were determined by competition analysis of [3H]bremazocine binding to membrane preparations. All compounds studied exhibited high affinity and selectivity, with apparent dissociation constants in the range of 0.6–1.7 nM for the δ opioid receptor and 240–1165 nM for the μ opioid receptor. We next sought to determine which domain of the δ receptor was critical for mediating the highly selective binding by analysis of ligand affinities for μ/δ receptor chimeras. Receptor binding profiles suggested that a critical site of receptor/ligand interaction was located between transmembrane domain 5 (TM5) and TM7 of the δ receptor. Substitution of tryptophan 284, located at the extracellular surface of TM6, with lysine, which is found at the equivalent position in the μ opioid receptor, led to a spectrum of effects on affinities, depending on the ligand tested. Affinities of SB 219825 and SB 222941 were particularly sensitive to the substitution, displaying a 50-fold and 70-fold decrease in affinity, respectively. Activities of the δ receptor-selective agonists were tested in two functional assays. Brief exposure of HEK 293 cells expressing δ opioid receptors with selective ligands induced phosphorylation of MAP kinase, although the non-peptidic ligands were less efficacious than the enkephalin derivative DADL (Tyr- d -Ala-Gly-Phe- d -Leu). Similarly, chronic exposure of HEK 293 cells expressing δ opioid receptors with selective, non-peptidic ligands, with the exception of SB 206848, caused receptor down-regulation, however, the SB compounds were less efficacious than DADL.

Discovery of potent and selective matrix metalloprotease 12 inhibitors for the potential treatment of chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with irreversible progressive airflow limitation. Matrix metalloproteinase-12 (MMP-12) has been characterized to be one of the major proteolytic enzymes to induce airway remodeling, destruction of elastin and the aberrant remodeling of damaged alveoli in COPD and asthma. The goal of this project is to develop and identify an orally potent and selective small molecule inhibitor of MMP-12 for treatment of COPD and asthma. Syntheses and structure-activity relationship (SAR) studies of a series of dibenzofuran (DBF) sulfonamides as MMP-12 inhibitors are described. Potent inhibitors of MMP-12 with excellent selectivity against other MMPs were identified. Compound 26 (MMP118), which exhibits excellent oral efficacy in the MMP-12 induced ear-swelling inflammation and lung inflammation mouse models, had been successfully advanced into Development Track status.

Neurokinin-3 receptor antagonists

Until late 1994, research on the neurokinin-3 (NK3) receptor, compared with that on neurokinin-1 (NK1) and neurokinin-2 (NK2) receptors, received little attention, due, to a large extent, to the absence of potent and selective non-peptide NK3 receptor antagonists. During 1995 and 1996, the disclosure of non-peptide antagonists led to a marked increase in research activities aimed at clarifying the physiological and pathophysiological role of the NK3 receptor. This review addresses the recent highlights and developments in this area, with particular emphasis on non-peptide NK3 receptor antagonists. Focus has been given to the various strategies utilised by several pharmaceutical companies to identify NK3 receptor antagonist prototypes and on the chemical optimisation processes which led to the potent and selective peptide-derived PD 161182 (8), the dichlorophenylalkylpiperidine SR 142,801 (9) and the quinoline derivative SB 223412 (27), which are representative compounds of the three distinct chemical clas...

Solid Phase Synthesis of Diamino-Substituted Pyrimidines

2,4- and 4,6-Diamino-substituted pyrimidines are known for their biological activity in many therapeutic areas. A novel solid-phase synthesis of this class of compounds by nucleophilic aromatic substitution has been set up and the reactivity of differently substituted solid-supported pyrimidines with properly selected amines has been studied. Using this methodology a small library of diamino-substituted pyrimidines has been prepared.

Pyrrolooctahydroisoquinolines as potent and selective ° opioid receptor ligands: SAR analysis and docking studies

Abstract Structure Activity Relationship and docking studies focused on the role of the non-aromatic ° address in a novel class of potent and selective ° ligands, pyrrolooctahydroisoquinolines, are discussed.

Investigation of SAR requirements of SR 142801 through an indexed combinatorial library in solution

To rapidly gain information on structure-activity relationship (SAR) requirements of the human neurokinin 3 (hNK-3) receptor antagonist SR 142801, an indexed combinatorial library was synthesised in solution and screened on the hNK-3 receptor. SAR considerations drawn from binding affinity of combinatorial mixtures were confirmed through the synthesis and biological evaluation of some individual compounds.

Ask the experts: future of the pharmaceutical industry. Interview by Future Medicinal Chemistry.

The pharmaceutical industry is facing numerous, well-documented challenges - from the effects of patent expirations to high attrition rates in the drug-development pipeline. Future Medicinal Chemistry has invited a group of leaders from academia and industry to express their views on where the industry is heading and speculate as to what role medicinal chemists will play in the future.