ABSTRACT
The identification of novel inhaled p38α/ß mitogen-activated protein kinases (MAPK) (MAPK14/11) inhibitors suitable for the treatment of pulmonary inflammatory conditions has been described. A rational drug design approach started from the identification of a novel tetrahydronaphthalene series, characterized by nanomolar inhibition of p38α with selectivity over p38γ and p38δ isoforms. SAR optimization of 1c is outlined, where improvements in potency against p38α and ligand-enzyme dissociation kinetics led to several compounds showing pronounced anti-inflammatory effects in vitro (inhibition of TNFα release). Targeting of the defined physicochemical properties allowed the identification of compounds 3h, 4e, and 4f, which showed, upon intratracheal instillation, low plasma levels, prolonged lung retention, and anti-inflammatory effects in a rat acute model of a bacterial endotoxin-induced pulmonary inflammation. Compound 4e, in particular, displayed remarkable efficacy and duration of action and was selected for progression in disease models of asthma and chronic obstructive pulmonary disease (COPD).
Subject(s)
Mitogen-Activated Protein Kinase 14 , Pneumonia , Protein Kinase Inhibitors , p38 Mitogen-Activated Protein Kinases , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Drug Design , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Phosphorylation , Pneumonia/drug therapy , Pneumonia/enzymology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Rats , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.
Subject(s)
Benzazepines/chemistry , Histamine H3 Antagonists/chemistry , Receptors, Histamine H3/chemistry , Animals , Benzazepines/chemical synthesis , Benzazepines/pharmacokinetics , Cytochrome P-450 CYP2D6/chemistry , Cytochrome P-450 CYP2D6/metabolism , Drug Evaluation, Preclinical , Half-Life , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Protein Binding , Rats , Receptors, Histamine H3/genetics , Receptors, Histamine H3/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Structure-Activity RelationshipABSTRACT
2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on T cells of S1P(1), one of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors, while its cardiovascular side effects have been associated with activity at S1P(3). Emerging data suggest that the ability of this molecule to cross the blood-brain barrier and to interact with both S1P(1) and S1P(5) in the central nervous system (CNS) may contribute to its efficacy in treating patients with RRMS. We have recently disclosed the structure of an advanced, first generation S1P(3)-sparing S1P(1) agonist, a zwitterion with limited CNS exposure. In this Article, we highlight our strategy toward the identification of CNS-penetrant S1P(3)-sparing S1P(1) and S1P(5) agonists resulting in the discovery of 5-(3-{2-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl}-1,2,4-oxadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile 15. Its exceptional in vivo potency and good pharmacokinetic properties translate into a very low predicted therapeutic dose in human (<1 mg p.o. once daily).
Subject(s)
Azepines/chemical synthesis , Brain/metabolism , Isoquinolines/chemical synthesis , Oxadiazoles/chemical synthesis , Receptors, Lysosphingolipid/agonists , Administration, Oral , Animals , Azepines/pharmacokinetics , Azepines/pharmacology , Biological Availability , Blood-Brain Barrier/metabolism , Cell Line , Cell Membrane Permeability , Dogs , Isoquinolines/pharmacokinetics , Isoquinolines/pharmacology , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Oxadiazoles/pharmacokinetics , Oxadiazoles/pharmacology , Rats , Receptors, Lysosphingolipid/metabolism , SolubilityABSTRACT
Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P1 and S1P3-5). It has been postulated that fingolimod's efficacy is due to S1P1 agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P3 agonism. We have discovered a series of selective S1P1 agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate, 20, a potent, S1P3-sparing, orally active S1P1 agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P3 is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.
ABSTRACT
A variety of basic, heterocyclic templates has been reported as potassium-competitive, acid pump antagonists. Herein, we report a comparison of potencies of these templates and others to establish which offers the best start point for further systematic optimisation. Modifications were carried out to improve the developability profile of the more potent 1H-pyrrolo[2,3-c]pyridine template, affording molecules with improved overall in vitro characteristics versus the reported clinical candidate AR-H047108, and comparable to the clinically efficacious AZD-0865.
Subject(s)
Heterocyclic Compounds/pharmacology , Proton Pump Inhibitors , Pyridines/pharmacology , Binding, Competitive , Drug Design , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Acid pump antagonists (APAs) such as the imidazo[1,2-a]pyridine AZD-0865 2 have proven efficacious at low oral doses in acid related gastric disorders. Herein we describe some of the broader SAR in this class of molecule and detail the discovery of an imidazo[1,2-a]pyridine 15 which has excellent efficacy in animal models of gastric acid secretion following oral administration, as well as a good overall developability profile. The discovery strategy focuses on use of heteroaryl and heterocyclic substituents at the C-6 position and optimization of developability characteristics through modulation of global physico-chemical properties.
Subject(s)
Proton Pump Inhibitors , Proton Pump Inhibitors/chemistry , Pyridines/chemistry , Administration, Oral , Animals , Dogs , H(+)-K(+)-Exchanging ATPase/metabolism , Humans , Hydrogen-Ion Concentration , Proton Pump Inhibitors/chemical synthesis , Proton Pump Inhibitors/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Increased Rho kinase (ROCK) activity contributes to smooth muscle contraction and regulates blood pressure homeostasis. We hypothesized that potent and selective ROCK inhibitors with novel structural motifs would help elucidate the functional role of ROCK and further explore the therapeutic potential of ROCK inhibition for hypertension. In this article, we characterized two aminofurazan-based inhibitors, GSK269962A [N-(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4, 5-c]pyridin-6-yl]oxy}phenyl)-4-{[2-(4-morpholinyl)ethyl]-oxy}benzamide] and SB-7720770-B [4-(7-{[(3S)-3-amino-1-pyrrolidinyl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine], as members of a novel class of compounds that potently inhibit ROCK enzymatic activity. GSK269962A and SB-772077-B have IC50 values of 1.6 and 5.6 nM toward recombinant human ROCK1, respectively. GSK269962A also exhibited more than 30-fold selectivity against a panel of serine/threonine kinases. In lipopolysaccharide-stimulated monocytes, these inhibitors blocked the generation of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha. Furthermore, both SB-772077-B and GSK269962A induced vasorelaxation in preconstricted rat aorta with an IC50 of 39 and 35 nM, respectively. Oral administration of either GSK269962A or SB-772077-B produced a profound dose-dependent reduction of systemic blood pressure in spontaneously hypertensive rats. At doses of 1, 3, and 30 mg/kg, both compounds induced a reduction in blood pressure of approximately 10, 20, and 50 mm Hg. In addition, administration of SB-772077-B also dramatically lowered blood pressure in DOCA salt-induced hypertensive rats. SB-772077-B and GSK269962A represent a novel class of ROCK inhibitors that have profound effects in the vasculature and may enable us to further evaluate the potential beneficial effects of ROCK inhibition in animal models of cardiovascular as well as other chronic diseases.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Imidazoles/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Oxadiazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Vasodilator Agents/pharmacology , Animals , Antihypertensive Agents/pharmacology , Cells, Cultured , Cytokines/biosynthesis , Humans , Macrophages/drug effects , Macrophages/immunology , Male , Rats , Rats, Inbred SHR , Rats, Inbred WKY , rho-Associated KinasesABSTRACT
A direct and versatile route for the reliable synthesis of trans-2,5-disubstituted pyrrolidines from pyroglutamic acid is reported, which can be conducted at scale and without chromatographic purification of key intermediates.