ABSTRACT
The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.
Subject(s)
Benzoic Acid/chemistry , Complement Factor B/antagonists & inhibitors , Indoles/chemistry , Atypical Hemolytic Uremic Syndrome/metabolism , Atypical Hemolytic Uremic Syndrome/pathology , Benzoic Acid/metabolism , Benzoic Acid/pharmacokinetics , Binding Sites , Catalytic Domain , Complement Factor B/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Half-Life , Humans , Indoles/metabolism , Indoles/pharmacokinetics , Inhibitory Concentration 50 , Macular Degeneration/metabolism , Macular Degeneration/pathology , Molecular Dynamics Simulation , Structure-Activity RelationshipABSTRACT
Diamide compounds were identified as potent DGAT1 inhibitors in vitro, but their poor molecular properties resulted in low oral bioavailability, both systemically and to DGAT1 in the enterocytes of the small intestine, resulting in a lack of efficacy in vivo. Replacing an N-alkyl group on the diamide with an N-aryl group was found to be an effective strategy to confer oral bioavailability and oral efficacy in this lipophilic diamide class of inhibitors.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Diamide/chemistry , Enzyme Inhibitors/chemistry , Animals , Cell Line, Tumor , Diacylglycerol O-Acyltransferase/metabolism , Diamide/chemical synthesis , Diamide/pharmacokinetics , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Half-Life , Humans , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A series of 6-aryl-3-pyrrolidinylpyridine analogs was explored as structurally novel negative allosteric modulators of the mGlu5 receptor lacking an alkyne or oxadiazole moiety. Compounds in this series were characterized by tractable SAR, good in vitro potencies and brain penetration in rodents.
Subject(s)
Pyridines/pharmacology , Pyrrolidines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Models, Molecular , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/blood , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A sequence of chemoselective activation of N-acylaminoacids, münchnone generation, intramolecular 1,3-dipolar cycloaddition, and ring opening efficiently generated functionalized polycyclic structures such as cyclopenta[b]pyrroles or zwitterionic bicyclo[4.3.0]nonane or bicyclo[3.3.0]octanes in one operation is given. These zwitterionic species were isolated for the first time and were subsequently reduced to bicyclic aminoalcohols. The effect of the substitution of both the dipolarophile and the münchnone on the intramolecular cycloaddition outcome was examined. It was found that either nonactivated or electron-poor alkenes can react with the münchnone if these alkenes are tethered at position 4 on the münchnone (2, R2 = alkene tether), whereas only an electron-poor alkene at position 2 (2, R3 = alkene tether) could undergo successful cycloaddition. Also, münchnones substituted at position 2 with a phenyl (2, R3 = Ph) showed a dramatic increase in reactivity, whereas a phenyl at position 4 (2, R2 = Ph) had a very limited effect.
