ABSTRACT
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.
