ABSTRACT
The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.
Subject(s)
COVID-19 Drug Treatment , Lactams/pharmacology , Lactams/therapeutic use , Leucine/pharmacology , Leucine/therapeutic use , Nitriles/pharmacology , Nitriles/therapeutic use , Proline/pharmacology , Proline/therapeutic use , SARS-CoV-2/drug effects , Viral Protease Inhibitors/pharmacology , Viral Protease Inhibitors/therapeutic use , Administration, Oral , Animals , COVID-19/virology , Clinical Trials, Phase I as Topic , Coronavirus/drug effects , Disease Models, Animal , Drug Therapy, Combination , Humans , Lactams/administration & dosage , Lactams/pharmacokinetics , Leucine/administration & dosage , Leucine/pharmacokinetics , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Nitriles/administration & dosage , Nitriles/pharmacokinetics , Proline/administration & dosage , Proline/pharmacokinetics , Randomized Controlled Trials as Topic , Ritonavir/administration & dosage , Ritonavir/therapeutic use , SARS-CoV-2/physiology , Viral Protease Inhibitors/administration & dosage , Viral Protease Inhibitors/pharmacokinetics , Virus Replication/drug effectsABSTRACT
Alterations in fat metabolism, in particular elevated plasma concentrations of free fatty acids and triglycerides (TG), have been implicated in the pathogenesis of Type 2 diabetes, obesity, and cardiovascular disease. Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a member of the large family of membrane-bound O-acyltransferases, catalyzes the final step in triacylglycerol formation. In the intestine, DGAT1 is one of the acyltransferases responsible for the reesterficiation of dietary TG. Following a single dose of a selective pharmacological inhibitor of DGAT1, PF-04620110, a dose-dependent inhibition of TG and vitamin A absorption postprandially was demonstrated in rodents and human subjects. In C57/BL6J mice, acute DGAT1 inhibition alters the temporal and spatial pattern of dietary lipid absorption. To understand the impact of DGAT1 inhibition on enterocyte lipid metabolism, lipomic profiling was performed in rat intestine and plasma as well as human plasma. DGAT1 inhibition causes an enrichment of polyunsaturated fatty acids within the TG class of lipids. This pharmacological intervention gives us insight as to the role of DGAT1 in human dietary lipid absorption.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Intestinal Absorption/drug effects , Oxazepines/pharmacology , Adolescent , Adult , Animals , Case-Control Studies , Diacylglycerol O-Acyltransferase/genetics , Diacylglycerol O-Acyltransferase/metabolism , Dietary Fats/blood , Dietary Fats/metabolism , Dose-Response Relationship, Drug , Enterocytes/metabolism , Enzyme Inhibitors/pharmacokinetics , Fatty Acids, Unsaturated/blood , Fatty Acids, Unsaturated/metabolism , Female , Humans , Intestinal Mucosa/metabolism , Lipid Metabolism/drug effects , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Oxazepines/pharmacokinetics , Postprandial Period , Rats , Rats, Sprague-Dawley , Triglycerides/blood , Triglycerides/metabolism , Vitamin A/metabolismABSTRACT
Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.