ABSTRACT
Anthranilamide analogues such as 23 are potent and highly selective muscarinic M2 antagonists that also show good oral bioavailability and in vivo activity.
Subject(s)
Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Receptor, Muscarinic M2/antagonists & inhibitors , ortho-Aminobenzoates/chemistry , Animals , Avoidance Learning/drug effects , Biochemistry/methods , Biological Availability , CHO Cells , Cricetinae , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Muscarinic Antagonists/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
The synthesis, SAR and biological evaluation of symmetrical amide analogues of our clinical candidate SCH 351125 are described. A series of potent and orally bioavailable CCR5 antagonists containing symmetrical 2,6-dimethyl isonicotinamides and 2, 6-dimethyl pyrimidines amides were generated with enhanced affinity for the CCR5 receptor.
Subject(s)
Amides/chemical synthesis , Anti-HIV Agents/chemical synthesis , CCR5 Receptor Antagonists , Heterocyclic Compounds, 3-Ring/chemical synthesis , Piperidines/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Animals , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/pharmacology , Chemokine CCL5/antagonists & inhibitors , Cyclic N-Oxides , Drug Evaluation, Preclinical , HIV-1/drug effects , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Inhibitory Concentration 50 , Oximes , Piperidines/pharmacokinetics , Piperidines/pharmacology , Pyridines , Rats , Structure-Activity RelationshipABSTRACT
The unsymmetrical nicotinamide-N-oxide moiety in compound 1 was replaced with symmetrical isonicotinamides as well as 4,6-dimethyl pyrimidine-5-carboxamides. Compound 16 from the latter set reduced the number of rotamers, improved potency of inhibiting UIV entry, slightly diminished the affinity for the muscarine receptors and showed very good oral absorption.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , HIV-1/drug effects , Piperazines/chemical synthesis , Piperazines/pharmacology , Administration, Oral , Animals , Anti-HIV Agents/pharmacokinetics , Area Under Curve , Chemical Phenomena , Chemistry, Physical , Half-Life , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacokinetics , Heterocyclic Compounds/pharmacology , Humans , Injections, Intravenous , Intestinal Absorption , Molecular Conformation , Piperazines/pharmacokinetics , Rats , Receptors, Muscarinic/drug effects , Structure-Activity RelationshipABSTRACT
We previously reported the initial discovery of a novel class of stabilized benzylidene ketal M(2) receptor antagonists. This paper discusses new analogues consisting of benzamide modifications which not only improved M(2) receptor affinity and selectivity, but also enhanced the pharmacokinetic properties of the series. These changes led to the discovery of a highly potent and selective M(2) antagonist, which demonstrated in vivo efficacy and had good bioavailability in multiple species.
Subject(s)
Benzamides/chemistry , Benzylidene Compounds/chemistry , Benzylidene Compounds/pharmacokinetics , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Receptors, Muscarinic/drug effects , Acetylcholine/analysis , Acetylcholine/biosynthesis , Animals , Area Under Curve , Benzamides/pharmacology , Drug Design , Drug Evaluation, Preclinical , Humans , Microdialysis , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Rats , Receptors, Muscarinic/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M(2) subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted.
