ABSTRACT
PF-184298 ((S)-2,3-dichloro-N-isobutyl-N-pyrrolidin-3-ylbenzamide) and PF-4776548 ((3-(4-fluoro-2-methoxy-benzyl)-7-hydroxy-8,9-dihydro-3H,7H-pyrrolo[2,3-c][1,7]naphthyridin-6-one)) are novel compounds which were selected to progress to human studies. Discordant human pharmacokinetic predictions arose from pre-clinical in vivo studies in rat and dog, and from human in vitro studies, resulting in a clearance prediction range of 3 to >20 mL min⻹ kg⻹ for PF-184298, and 5 to >20 mL min⻹ kg⻹ for PF-4776548. A package of work to investigate the discordance for PF-184298 is described. Although ultimately complementary to the human pharmacokinetic data in characterising the disposition of PF-184298 in humans, these data did not provide any further confidence in pharmacokinetic prediction. A fit for purpose human pharmacokinetic study was conducted for each compound, with an oral pharmacologically active dose for PF-184298, and an intravenous and oral microdose for PF-4776548. This provided a relatively low cost, clear decision making approach, resulting in the termination of PF-4776548 and further progression of PF-184298. A retrospective analysis of the data showed that, if the tools had been available at the time, the pharmacokinetics of PF-184298 in human could have been predicted from a population based simulation tool in combination with physicochemical properties and in vitro human intrinsic clearance.
Subject(s)
Anilides/pharmacokinetics , Drug Evaluation, Preclinical/methods , Models, Biological , Naphthyridines/pharmacokinetics , Pyrrolidines/pharmacokinetics , Adult , Anilides/administration & dosage , Animal Testing Alternatives , Animals , Dogs , Drug Discovery , Humans , Male , Microsomes, Liver/metabolism , Naphthyridines/administration & dosage , Pharmacokinetics , Pyrrolidines/administration & dosage , Rats , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Statistics as Topic , Young AdultABSTRACT
Lersivirine is a potent non-nucleoside reverse transcriptase inhibitor with exceptional mutant resilience. Here, we compare the pharmacological and pharmacokinetic profile of lersivirine with its pyrazole and imidazole isomers and briefly explore the profile of these series. This work establishes lersivirine as the outstanding molecule in this set.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , Imidazoles/pharmacokinetics , Microsomes, Liver/drug effects , Nitriles/pharmacokinetics , Pyrazoles/pharmacokinetics , Reverse Transcriptase Inhibitors/pharmacokinetics , Animals , Drug Design , HIV Infections/drug therapy , HIV Infections/virology , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , HIV-1/enzymology , HIV-1/genetics , Humans , Imidazoles/chemistry , Microsomes, Liver/enzymology , Models, Molecular , Mutation , Nitriles/chemistry , Pyrazoles/chemistry , Rats , Reverse Transcriptase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
The structure-activity relationship and the synthesis of novel N-[(3S)-pyrrolidin-3-yl]benzamides as dual serotonin and noradrenaline monoamine reuptake inhibitors (SNRI) is described. Preferred compound 9 aka PF-184,298 is a potent SNRI with good selectivity over dopamine reuptake inhibition (DRI), good in vitro metabolic stability, weak CYP inhibition and drug-like physicochemical properties consistent with CNS target space. Evaluation in an in vivo preclinical model of stress urinary incontinence showed 9 significantly increased urethral tone at free plasma concentrations consistent with its in vitro primary pharmacology.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adrenergic Uptake Inhibitors/chemistry , Anilides/chemistry , Benzamides/chemistry , Central Nervous System/metabolism , Pyrrolidines/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacokinetics , Anilides/chemical synthesis , Anilides/pharmacology , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Cell Line , Dogs , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacokinetics , Humans , Norepinephrine/metabolism , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Rats , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their lack of resilience to mutations in the reverse transcriptase (RT) enzyme. Using structural overlays of the known inhibitors efavirenz and capravirine complexed in RT as a starting point, and structure-based drug design techniques, we have created a novel series of indazole NNRTIs that possess excellent metabolic stability and mutant resilience.
Subject(s)
Anti-HIV Agents/chemistry , Indazoles/chemistry , Reverse Transcriptase Inhibitors/chemistry , Alkynes , Anti-HIV Agents/pharmacology , Benzoxazines/pharmacology , Crystallography, X-Ray , Cyclopropanes , Drug Design , Drug Resistance, Viral/drug effects , Drug Resistance, Viral/genetics , Drug Stability , HIV/drug effects , HIV/enzymology , HIV/genetics , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/genetics , Humans , Imidazoles/pharmacology , Indazoles/pharmacology , Molecular Structure , Mutation , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity Relationship , Sulfur Compounds/pharmacologyABSTRACT
A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their vulnerability to mutations in the allosteric binding site of reverse transcriptase that can result in the development of a resistant virus. Herein we present the optimization of a series of 5-aryloxy imidazoles, which possess a balanced pharmacological profile against both wild-type enzyme and the clinically relevant mutations K103N and Y181C. Subtle structural changes were used to probe structure-activity relationships relating to both potency and metabolic stability, which led to an imidazole derivative with an impressive overall profile.
