ABSTRACT
In our continuing efforts to explore structure-activity relationships around the novel class of potent, isonicotinamide-based GSK3 inhibitors described in our previous report, we extensively explored structural variations around both 4/5-pyridine substitutions and the amide group. Some analogs were found to have greatly improved pTau lowering potency while retaining high kinase selectivity. In contrast to previous active compounds 1a-c, a close analog 3h did not show in vivo efficacy in a triple-transgenic mouse Alzheimer's disease model. In general, these 2pyridinyl amide derivatives were prone to amidase mediated hydrolysis in mouse plasma.
Subject(s)
Alzheimer Disease , Glycogen Synthase Kinase 3 , Mice , Animals , Structure-Activity Relationship , Mice, Transgenic , Amides/pharmacology , Glycogen Synthase Kinase 3 beta , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistryABSTRACT
Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1'-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1' group. Over the course of the optimization efforts, the 1-(1H-tetrazol-5-yl)cyclopropane P1' substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity.
Subject(s)
Factor VIIa/antagonists & inhibitors , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Thromboplastin/antagonists & inhibitors , Animals , Dogs , Drug Design , Humans , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Inhibitors of the tissue factor (TF)/factor VIIa complex (TF-FVIIa) are promising novel anticoagulants which show excellent efficacy and minimal bleeding in preclinical models. Starting with an aminoisoquinoline P1-based macrocyclic inhibitor, optimization of the P' groups led to a series of highly potent and selective TF-FVIIa inhibitors which displayed poor permeability. Fluorination of the aminoisoquinoline reduced the basicity of the P1 group and significantly improved permeability. The resulting lead compound was highly potent, selective, and achieved good pharmacokinetics in dogs with oral dosing. Moreover, it demonstrated robust antithrombotic activity in a rabbit model of arterial thrombosis.
Subject(s)
Anticoagulants/pharmacology , Drug Discovery , Factor VIIa/antagonists & inhibitors , Macrocyclic Compounds/pharmacology , Thromboplastin/antagonists & inhibitors , Administration, Oral , Animals , Anticoagulants/administration & dosage , Anticoagulants/chemistry , Biological Availability , Dogs , Dose-Response Relationship, Drug , Factor VIIa/metabolism , Healthy Volunteers , Humans , Macrocyclic Compounds/administration & dosage , Macrocyclic Compounds/chemistry , Male , Models, Molecular , Molecular Structure , Rabbits , Structure-Activity Relationship , Thromboplastin/metabolismABSTRACT
Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3ß. We identified several series of promising new GSK-3ß inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3ß inhibitors. When dosed orally in a transgenic mouse model of Alzheimer's disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses.
Subject(s)
Aminopyridines/pharmacology , Drug Discovery , Glycogen Synthase Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridones/chemistry , Pyrroles/chemistry , Aminopyridines/administration & dosage , Aminopyridines/chemistry , Animals , Crystallography, X-Ray , Disease Models, Animal , Dose-Response Relationship, Drug , Glycogen Synthase Kinase 3/metabolism , Humans , Mice , Mice, Transgenic , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel anticoagulants that show excellent efficacy and minimal bleeding in preclinical models. On the basis of a zwitterionic phenylglycine acylsulfonamide 1, a phenylglycine benzylamide 2 was shown to possess improved permeability and oral bioavailability. Optimization of the benzylamide, guided by X-ray crystallography, led to a potent TF-FVIIa inhibitor 18i with promising oral bioavailability, but promiscuous activity in an in vitro safety panel of receptors and enzymes. Introducing an acid on the pyrrolidine ring, guided by molecular modeling, resulted in highly potent, selective, and efficacious TF-FVIIa inhibitors with clean in vitro safety profile. The pyrrolidine acid 20 showed a moderate clearance, low volume of distribution, and a short t 1/2 in dog PK studies.
ABSTRACT
The identification, optimization, and structure-activity relationship (SAR) of small-molecule CCR4 antagonists is described. An initial screening hit with micromolar potency was identified that was optimized to sub-micromolar binding potency by enantiomer resolution, halogenation of the naphthalene ring, and extension of the alkyl chain linker between the central piperidine ring and the terminal aryl group. An antagonist was identified that showed good cross-reactivity against the mouse receptor and inhibited CCR4-based cell recruitment in dose-dependent fashion.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Naphthalenes/chemistry , Naphthalenes/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Mice , Mice, Inbred BALB C , Naphthalenes/chemical synthesis , Receptors, CCR4 , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
The design, synthesis, and structure-activity relationship development of naphthalene-derived human CCR8 antagonists is described. In vitro binding assay results of these investigations are reported, critical interactions of the antagonists with CCR8 are defined, and preliminary physicochemical and pharmacokinetic data for the naphthalene scaffold are presented.
Subject(s)
Naphthalenes/chemical synthesis , Receptors, Chemokine/antagonists & inhibitors , Sulfonamides/chemical synthesis , Administration, Oral , Animals , Biological Availability , Biological Transport , Calcium/metabolism , Cell Line , Cricetinae , Cricetulus , Drug Design , Humans , Naphthalenes/pharmacokinetics , Naphthalenes/pharmacology , Rats , Receptors, CCR8 , Solubility , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacologyABSTRACT
Dinapsoline is a full D(1) dopamine receptor agonist that produces robust rotational activity in the unilateral 6-OHDA rat model. This compound is orally active, and shows a low tendency to cause tolerance in rat models. The active enantiomer was determined to have the S-(+) configuration, and the opposite enantiomer is essentially devoid of biological activity. Taken together, dinapsoline has significant metabolic and pharmacological advantages over previous D(1) agonists. In an attempt to define the structure-activity relationships (SARs) and to map out the key elements surrounding the unique structure of dinapsoline, core analogues and substitution analogues of the parent tetracyclic condensed ring structure were prepared. Based on a recently developed synthesis of dinapsoline and its enantiomers, both core and substitution analogues on all four rings (A, B', C and D ring) of dinapsoline were synthesized. It was found that affinity for both D(1)and D(2) receptors was decreased by most substituents on the A, B', and C rings, whereas D ring substitutions preserved much of the dopamine receptor binding activity.
Subject(s)
Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Naphthols/chemical synthesis , Naphthols/pharmacology , Adenylyl Cyclases/metabolism , Animals , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Aza Compounds/pharmacology , Cells, Cultured , Fluorine/chemistry , Isoquinolines/chemistry , Molecular Structure , Naphthols/chemistry , Rats , Structure-Activity RelationshipABSTRACT
A highly convergent synthesis was developed for the novel dopamine agonist dinapsoline (12) (Ghosh, D.; Snyder, S. E.; Watts, V. J.; Mailman, R. B.; Nichols, D. E. 8,9-Dihydroxy-2,3,7, 11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline: A Potent Full Dopamine D(1) Agonist Containing a Rigid beta-Phenyldopamine Pharmacophore. J. Med. Chem. 1996, 39 (2), 549-555). The crucial step in the new synthesis was a free radical-initiated cyclization to give the complete dinapsoline framework. The improved synthesis required half as many steps as the original procedure (Nichols, D. E.; Mailman, R.; Ghosh, D. Preparation of novel naphtho[1,2,3-de]isoquinolines as dopamine receptor ligands. PCT Int. Appl. WO 9706799 A1, Feb 27, 1997). One of the late-stage intermediates (11) was resolved into a pair of enantiomers. From there, the (R)-(+)-12 (absolute configuration by X-ray) of dinapsoline was identified as the active enantiomer. In unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats, (+)-dinapsoline showed robust rotational behavior comparable to that of an external benchmark, trans-4,5,5a,6,7,11b-hexahydro-2-propyl-benzo[f]thieno[2,3-c]quinoline-9,10-diol, hydrochloride 18 (Michaelides, M. R.; Hong, Y. Preparation of heterotetracyclic compounds as dopamine agonists. PCT Int. Appl. WO 9422858 A1, Oct 13, 1994).