ABSTRACT
Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.
Subject(s)
Anti-HIV Agents/chemical synthesis , Azabicyclo Compounds/chemical synthesis , CCR5 Receptor Antagonists , HIV-1/drug effects , Imidazoles/chemical synthesis , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacology , Cell Line , Cricetinae , Cyclohexanes/pharmacology , Dogs , Drug Resistance, Viral , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , HIV-1/isolation & purification , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/virology , Maraviroc , Models, Molecular , Protein Binding , Rats , Stereoisomerism , Structure-Activity Relationship , Triazoles/pharmacology , TropanesABSTRACT
This Letter reports the design and synthesis of several novel series of piperazinyl pyrimidinones as 5-HT(2C) agonists. Several of the compounds presented exhibit good in vitro potency and selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compound 11 was active in in vivo models of stress urinary incontinence.
Subject(s)
Pyrimidinones/chemistry , Pyrimidinones/therapeutic use , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/therapeutic use , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Humans , Pyrimidinones/pharmacology , Receptor, Serotonin, 5-HT2B/metabolism , Serotonin Receptor Agonists/pharmacology , Structure-Activity Relationship , Urethra/drug effects , Urinary Incontinence/drug therapyABSTRACT
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists is described leading through to human pharmacokinetic data for a clinical candidate.
Subject(s)
Adenosine A2 Receptor Agonists , Pulmonary Disease, Chronic Obstructive/drug therapy , Adenosine/analogs & derivatives , Adenosine/chemistry , Administration, Inhalation , Adolescent , Adult , Animals , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inhibitory Concentration 50 , Lung/drug effects , Male , Middle Aged , Models, Chemical , Phenethylamines/chemistry , Purines/chemistry , Rats , Structure-Activity Relationship , Triazoles/chemistryABSTRACT
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained.
Subject(s)
Adenosine A2 Receptor Agonists , Adenosine/analogs & derivatives , Pulmonary Disease, Chronic Obstructive/drug therapy , Adenosine/pharmacokinetics , Adenosine/pharmacology , Administration, Inhalation , Administration, Oral , Amines/pharmacokinetics , Amines/pharmacology , Animals , Guinea Pigs , Humans , Lung/metabolism , Phenethylamines/pharmacokinetics , Phenethylamines/pharmacology , Pulmonary Disease, Chronic Obstructive/metabolism , Rats , Structure-Activity RelationshipABSTRACT
This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.
