ABSTRACT
Direct-acting antiviral regimens have transformed therapeutic management of hepatitis C across all prevalent genotypes. Most of the chemical matter in these regimens comprises molecules well outside the traditional drug development chemical space and presents significant challenges. Herein, the implications of high conformational flexibility and the presence of a 15-membered macrocyclic ring in paritaprevir are studied through a combination of advanced computational and experimental methods with focus on molecular chameleonicity and crystal form complexity. The ability of the molecule to toggle between high and low 3D polar surface area (PSA) conformations is underpinned by intramolecular hydrogen bonding (IMHB) interactions and intramolecular steric effects. Computational studies consequently show a very significant difference of over 75 Å2 in 3D PSA between polar and apolar environments and provide the structural basis for the perplexingly favorable passive permeability of the molecule. Crystal packing and protein binding resulting in strong intermolecular interactions disrupt these intramolecular interactions. Crystalline Form I benefits from strong intermolecular interactions, whereas the weaker intermolecular interactions in Form II are partially compensated by the energetic advantage of an IMHB. Like Form I, no IMHB is observed within the receptor-bound conformation; instead, an intermolecular H-bond contributes to the potency of the molecule. The choice of metastable Form II is derisked through strategies accounting for crystal surface and packing features to manage higher form specific solid-state chemical reactivity and specific processing requirements. Overall, the results show an unambiguous link between structural features and derived properties from crystallization to dissolution, permeation, and docking into the protein pocket.
ABSTRACT
Two syntheses of 3-substituted-4-amino-[3,2-c]thienopyridines have been developed to replace the standard literature route to these compounds, which uses unattractive conditions involving azide and high temperatures. The first synthesis utilizes a Friedel-Crafts reaction as its key ring-forming step, whereas the second route relies on an unprecedented intramolecular reductive cyclization between a nitroolefin and a nitrile as its key ring-forming step. The development and optimization of each 3-substituted-4-amino-[3,2-c]thienopyridine synthesis is discussed and a comparison of the routes is presented.
Subject(s)
Pyridines/chemical synthesis , Carbon Dioxide/chemistry , Cyclization , Halogens/chemistry , Metals/chemistry , Oxidation-Reduction , Pyridines/chemistry , Thiophenes/chemistryABSTRACT
A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Cycloheptanes/chemical synthesis , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Hypolipidemic Agents/chemical synthesis , Keto Acids/chemical synthesis , Urea/analogs & derivatives , Urea/chemical synthesis , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacokinetics , Biphenyl Compounds/pharmacology , Cycloheptanes/pharmacokinetics , Cycloheptanes/pharmacology , Diacylglycerol O-Acyltransferase/genetics , Eating/drug effects , Humans , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/pharmacology , Isoenzymes/antagonists & inhibitors , Isoenzymes/genetics , Keto Acids/pharmacokinetics , Keto Acids/pharmacology , Liver/metabolism , Mice , Mice, Mutant Strains , Stereoisomerism , Structure-Activity Relationship , Triglycerides/metabolism , Urea/pharmacokinetics , Urea/pharmacology , Weight LossABSTRACT
A gram scale synthesis of the glucuronide metabolite of ABT-724 is reported. Glycosidic coupling between a trichloroacetimidate glucuronyl donor and a Cbz-protected hydroxypyridylpiperazine glycosyl acceptor is the key step in the synthesis, since attempts to directly glucuronidate the aglycon, aglycon derivatives, and other truncated glycosyl acceptors were unsuccessful. The route was used to produce 2.1 g of metabolite in eight steps from 2-chloro-5-hydroxypyridine in 21% overall yield.
Subject(s)
Benzimidazoles/chemistry , Glucuronides/chemistry , Glucuronides/chemical synthesis , Piperazines/chemistry , Pyridines/chemistry , Benzimidazoles/metabolism , Dopamine Agonists/chemistry , Dopamine Agonists/metabolism , Esters/chemistry , Esters/metabolism , Glucuronides/metabolism , Molecular Structure , Piperazines/metabolism , Pyridines/metabolismABSTRACT
The synthesis and biological evaluation of novel 3-amino indazole melanin concentrating hormone receptor-1 antagonists are reported, several of which demonstrated functional activity of less than 100nM. Compounds 19 and 28, two of the more potent compounds identified in this study, were characterized by high exposure in the brain and demonstrated robust efficacy when dosed in diet-induced obese mice.
