Robert Toms Jacobs

Chapter 12. Pulmonary and Anti-Allergy Agents

Publisher Summary Investigations of neuropeptide antagonists as an approach to the treatment of asthma have gained momentum with the discovery of non-peptidic tachykinin antagonists. The literature debate over the role of β-adrenergic agonists in the treatment of asthma has intensified. However, results from a new study suggest that inhaled β-agonists are indeed associated with higher mortality, and that is an effect common to all β-agonists. The current status of research on leukotriene antagonists and their role in asthma have been reviewed in this chapter. Clinical studies have showed that ICI 204,219, given orally, could reduce antigen-induced bronchoconstriction in asthmatic patients. Zileuton, dosed orally to atopic asthmatics, only partially inhibited allergen-induced 5-lipoxygenase (5-LO) activity in vivo , despite almost complete ex vivo 5-LO inhibition. The development of thromboxane receptor antagonists (TXRAs) has been reviewed. Oral administration of the TXRA AA-2414 to asthmatic subjects favorably attenuated their response to methacholine challenge. The potential effects of platelet-activating factor (PAF) on pulmonary function through activation of human eosinophils, neutrophils, and macrophages have been examined. In a separate trial, oral dosing of the hetrazepine PAF antagonist apafant (WEB-2086) in humans provided potent inhibition of in vivo cutaneous and ex vivo platelet responses to PAF. The basic pharmacology and clinical results from several important second-generation histamine antagonists are summarized in this chapter. Recent studies on some of these agents have shown that they may possess characteristics in addition to their ability to antagonize histamine receptors. The search for applications of potassium channel openers in asthma has continued. Bradykinin and bradykinin antagonists have received increased attention and been the subject of several recent reviews. The role of tachykinins in pulmonary diseases is also reviewed in the chapter.

4-Alkylpiperidines related to SR-48968: Potent antagonists of the neurokinin-2 (NK2) receptor

A series of 4-alkylpiperidine derivatives related to the potent neurokinin-2 (NK2) receptor antagonist SR-48968 (1) is described. Simple aliphatic derivatives were found to be poorly active, but appropriate placement of an alcohol functional group afforded compounds that were of similar activity to 1. Several representatives in this series, such as the 4-(1-hydroxy-1-ethylpropyl)piperidine (14), were found to exhibit oral activity in a model of labored abdominal breathing in guinea pigs. These results expand the latitude of substituents available in this region of this series of NK2 receptor antagonists.

Substituted 2,4-diaminoquinazolines and 2,4-diamino-8-alkylpurines as antagonists of the neurokinin-2 (NK2) receptor

Abstract Modification of the heterocyclic nucleus of a lead pyrrolopyrimidine (1) found to be active as an antagonist at the neurokinin-2 (NK2) receptor is described. Compounds based on the purine nucleus (3) were found to be particularly interesting, and were modified in the C(2), C(4) and C(8) substituents to afford compounds with high potency.

Putative atypical antipsychotics with mixed dopaminergic (D1, D2) and serotonergic (5HT2) activity: The design evolution of ZD3638

Abstract The pharmacological activity of a series of 9,10-dihydro-9,10-methanoanthracene methylene amines which function as mixed dopaminergic (D1/D2) and serotonergic (5HT2) antagonists is described. The work resulted in a putative atypical antipsychotic, ZD3638, of novel structure and pharmacological profile.