ABSTRACT
Soluble guanylate cyclase (sGC) is a clinically validated therapeutic target in the treatment of pulmonary hypertension. Modulators of sGC have the potential to treat diseases that are affected by dysregulation of the NO-sGC-cGMP signal transduction pathway. This letter describes the SAR efforts that led to the discovery of CYR715, a novel carboxylic acid-containing sGC stimulator, with an improved metabolic profile relative to our previously described stimulator, IWP-051. CYR715 addressed potential idiosyncratic drug toxicity (IDT) liabilities associated with the formation of reactive, migrating acyl glucuronides (AG) found in related carboxylic acid-containing analogs and demonstrated high oral bioavailability in rat and dose-dependent hemodynamic pharmacology in normotensive Sprague-Dawley rats.
Subject(s)
Carboxylic Acids/chemistry , Glucuronides/chemistry , Hypertension, Pulmonary/drug therapy , Soluble Guanylyl Cyclase/metabolism , Vasodilator Agents/chemistry , Administration, Oral , Animals , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Glucuronides/administration & dosage , Glucuronides/pharmacokinetics , Humans , Male , Metabolome , Models, Molecular , Nitric Oxide/metabolism , Oxidative Stress/drug effects , Protein Binding , Rats, Sprague-Dawley , Signal Transduction , Structure-Activity Relationship , Vasodilator Agents/administration & dosage , Vasodilator Agents/pharmacokineticsABSTRACT
MM-433593 is a highly potent and selective inhibitor of fatty acid amide hydrolase-1 (FAAH-1) with potential utility as an orally administered treatment of pain, inflammation, and other disorders. In this study, we investigated the metabolism and pharmacokinetics of MM-433593 in monkeys, and compared plasma and urine metabolites of this compound to the in vitro metabolites produced by monkey hepatocytes. Intravenous administration of MM-433593 to cynomolgus monkeys produced a rapid distribution phase and slower elimination phase with a mean systemic clearance rate of 8-11 mL/min/kg. Absolute oral bioavailability was determined to be 14-21% with maximum plasma concentrations reached â¼3 h (T max) following a 10 mg/kg oral dose. The average terminal half-life of MM-433593 was 17-20 h, and there were no qualitative sex differences in the metabolite profile of MM-433593. The major site of metabolism was oxidation of the methyl group at the five position of the indole ring, which was confirmed by chromatography and mass spectrometry comparison to a synthesized authentic standard. This metabolite was further oxidized to the corresponding carboxylic acid and/or conjugated with sulfate, glucuronide, or glutathione. In all, 18 metabolites were found in plasma and urine. In vitro incubations of MM-433593 with monkey hepatocytes yielded 13 metabolites, all of which were found in vivo, indicating a good correlation between the in vitro and in vivo metabolism data. A comprehensive pathway for the metabolism of MM-433593 is proposed, including a plausible, five-step biotransformation for the formation of N-acetylcysteine conjugate metabolite (M18) from the hydroxylated parent (M5).
ABSTRACT
3-Amino-2-keto-7H-thieno[2,3-b]pyridin-6-one derivatives were discovered as moderately potent inhibitors of ubiquitin C-terminal hydrolase-L1 (UCH-L1) utilizing an assay that measures hydrolysis of the fluorogenic substrate Ub-AMC. SAR studies revealed that both the carboxylate at the 5-position and the 6-pyridone ring were critical for inhibitory activity. Furthermore, activity was dependent on the nature of the ketone substituent at the 2-position, with 4-Me-Ph and 2-naphthyl being best. Kinetic mechanism studies revealed that these compounds were uncompetitive inhibitors of UCH-L1, binding only to the Michaelis-complex and not to free enzyme. The active compounds were selective for UCH-L1, exhibiting neither inhibition of other cysteine hydrolases (e.g., UCH-L3, papain, isopeptidase T, caspase-3, and tissue transglutaminase) nor cytotoxicity in N2A cells.
Subject(s)
Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Ubiquitin Thiolesterase/antagonists & inhibitors , Cell Line, Tumor , Cysteine/chemistry , Drug Design , Enzyme Inhibitors/chemistry , Humans , Ketones/chemistry , Kinetics , Models, Chemical , Protein Binding , Structure-Activity Relationship , Substrate Specificity , Ubiquitin Thiolesterase/chemistryABSTRACT
With the aid of an appropriate chiral catalyst, acyclic silyl ketene acetals react with anhydrides to furnish 1,3-dicarbonyl compounds that bear all-carbon quaternary stereocenters in good ee and yield. Mechanistic studies provide strong support for a catalytic cycle that involves activation of both the electrophile (anhydride --> acylpyridinium) and the nucleophile (silyl ketene acetal --> enolate).
Subject(s)
Acetals/chemistry , Ethylenes/chemistry , Ketones/chemistry , Silanes/chemistry , Acylation , Anhydrides/chemistry , Catalysis , Pyridinium Compounds/chemistry , StereoisomerismABSTRACT
A nucleophile-catalyzed asymmetric intermolecular C-acylation of silyl ketene acetals by anhydrides has been developed, furnishing quaternary stereocenters with high enantioselectivity. Mechanistic studies support the hypothesis that the reaction involves activation both of the silyl ketene acetal (generation of an enolate) and of the anhydride (formation of an acylpyridinium ion).
