ABSTRACT
Leukotriene A4 (LTA4) hydrolase is a zinc-containing enzyme which stereospecifically catalyzes the hydrolysis of the epoxide LTA4 to the diol leukotriene B4 (LTB4). There is substantial evidence that LTB4 plays a significant role in the amplification of many inflammatory disease states. Therapeutic agents which selectively inhibit LTA4 hydrolase would block the formation of LTB4 and thus be potentially useful for the treatment of inflammation. Numerous inhibitors of LTA4 hydrolase have been reported over the past 15-20 years. Several early inhibitors were based on the structure of the natural substrate, LTA4. Later approaches utilized known inhibitors of related zinc-containing metalloproteinases and led to the identification of captopril, bestatin and kelatorphan as potent inhibitors of LTA4 hydrolase. This led to the design of a number of peptide and non-peptide analogs which contained potential zinc-chelating moieties, including thiols, hydroxamates and norstatines. A more recent series of non-peptidic, non-zinc chelating inhibitors of LTA4 hydrolase has been reported. This work led to the identification of several novel classes of analogs, including imidazopyridines, amidines and cyclic and acyclic amino acid derivatives, ultimately resulting in the identification of two potential clinical candidates SC-56938 and SC-57461A.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Enzyme Inhibitors/pharmacology , Epoxide Hydrolases/antagonists & inhibitors , Amidines/chemistry , Amidines/pharmacology , Amino Acids/chemistry , Amino Acids/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Epoxide Hydrolases/metabolism , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Molecular Structure , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Zinc/metabolism , beta-Alanine/analogs & derivatives , beta-Alanine/chemistry , beta-Alanine/pharmacologyABSTRACT
Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Epoxide Hydrolases/antagonists & inhibitors , Pyrrolidines/chemical synthesis , Administration, Oral , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , In Vitro Techniques , Leukotriene B4/biosynthesis , Leukotriene B4/blood , Male , Mice , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Structure-Activity RelationshipABSTRACT
A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.
Subject(s)
Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacology , Isoenzymes/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Animals , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Carrageenan/pharmacology , Celecoxib , Cyclooxygenase 1 , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase Inhibitors/pharmacokinetics , Hyperalgesia/drug therapy , Magnetic Resonance Spectroscopy , Male , Membrane Proteins , Molecular Structure , Osteoarthritis/drug therapy , Pyrazoles , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Prostaglandins and glucocorticoids are potent mediators of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effects by inhibition of prostaglandin production. The pharmacological target of NSAIDs is cyclooxygenase (COX, also known as PGH synthase), which catalyses the first committed step in arachidonic-acid metabolism. Two isoforms of the membrane protein COX are known: COX-1, which is constitutively expressed in most tissues, is responsible for the physiological production of prostaglandins; and COX-2, which is induced by cytokines, mitogens and endotoxins in inflammatory cells, is responsible for the elevated production of prostaglandins during inflammation. The structure of ovine COX-1 complexed with several NSAIDs has been determined. Here we report the structures of unliganded murine COX-2 and complexes with flurbiprofen, indomethacin and SC-558, a selective COX-2 inhibitor, determined at 3.0 to 2.5 A resolution. These structures explain the structural basis for the selective inhibition of COX-2, and demonstrate some of the conformational changes associated with time-dependent inhibition.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase Inhibitors/pharmacology , Isoenzymes/chemistry , Prostaglandin-Endoperoxide Synthases/chemistry , Animals , Cell Line , Cloning, Molecular , Crystallography, X-Ray , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Flurbiprofen/pharmacology , Indomethacin/pharmacology , Mice , Models, Molecular , Protein Conformation , Pyrazoles/pharmacology , Structure-Activity RelationshipABSTRACT
Leukotriene B4 (LTB4) and 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE] are proinflammatory products of arachidonic acid metabolism that have been implicated as mediators in a number of inflammatory diseases. When injected intradermally into the guinea pig. LTB4 and 12(R)-HETE elicit a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxyl]-3,4-dihy dro-8-propyl-2H - 1-benzopyran-2-carboxylic acid), a first-generation LTB4 receptor antagonist, inhibited the chemotactic actions of LTB4 when given orally with an ED50 value of 1.7 mg/kg. The second-generation LTB4 receptor antagonist, SC-53228 [(+)-(S)-7-(3-(2-(cyclopropylmethyl)-3-methoxy-4- [(methylamino)carbonyl]phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1- benzopyran-2-propanoic acid], inhibited LTB4-induced chemotaxis when given intragastrically with an ED50 value of 0.07 mg/kg. Furthermore, SC-53228 inhibited 12(R)-HETE-induced granulocyte chemotaxis with an oral ED50 value of 5.8 mg/kg. When dosed orally over a range of 0.03-100 mg/kg, SC-53228 gave Cmax plasma concentrations of 0.015-41.1 micrograms/ml. SC-53228 inhibited LTB4-primed membrane depolarization of human neutrophils with an IC50 value of 34 nM. As a potent LTB4 receptor antagonist, SC-53228 may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, in which LTB4 and/or 12(R)-HETE are implicated as inflammatory mediators.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzamides/pharmacology , Benzopyrans/pharmacology , Chemotaxis, Leukocyte/drug effects , Hydroxyeicosatetraenoic Acids/pharmacology , Leukotriene B4/pharmacology , Receptors, Leukotriene B4/antagonists & inhibitors , Skin/drug effects , 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Benzamides/administration & dosage , Benzopyrans/administration & dosage , Biomarkers , Granulocytes/drug effects , Guinea Pigs , Hydroxyeicosatetraenoic Acids/administration & dosage , Injections, Intradermal , Leukotriene B4/administration & dosage , Male , Membrane Potentials/drug effects , Neutrophils/drug effects , Neutrophils/enzymology , Peroxidase/analysis , Receptors, Leukotriene B4/physiology , Skin/immunology , Skin/pathologyABSTRACT
Our previous reports have highlighted the first-generation leukotriene B4 (LTB4) receptor antagonist SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]3,4- dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid) which has potent oral, topical, and intracolonic activity in various animal models of inflammation. Extensive structure-activity relationship studies, in which a series of heterocyclic replacements for the methyl ketone functional group of SC-41930 was explored, identified SC-50605 (7-[3-[2-(cyclopropylmethyl)-3-methoxy-4- (4-thiazolyl)phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2- carboxylic acid) as an optimized analog within a series of thiazoles. SC-50605 was found to be significantly more potent than SC-41930 in LTB4 receptor binding, chemotaxis, and degranulation assays. It also displayed very good activity in animal models of colitis and epidermal inflammation by oral, topical, intravenous, and intracolonic routes of administration. The resolved enantiomers of SC-50605 were obtained by chiral chromatography and both demonstrated good in vitro and in vivo activity. The (+)-isomer (SC-52798) is currently being evaluated as a potential clinical candidate for psoriasis and ulcerative colitis therapy.
Subject(s)
Azoles/chemical synthesis , Azoles/pharmacology , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Receptors, Leukotriene B4/antagonists & inhibitors , Amino Acid Sequence , Animals , Azoles/metabolism , Benzopyrans/metabolism , Chemotactic Factors/chemical synthesis , Chemotactic Factors/pharmacology , Guinea Pigs , Humans , Mice , Molecular Sequence Data , N-Formylmethionine Leucyl-Phenylalanine/metabolism , N-Formylmethionine Leucyl-Phenylalanine/pharmacology , Receptors, Leukotriene B4/metabolism , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/metabolism , Thiazoles/pharmacologyABSTRACT
Leukotriene B4 (LTB4) is a proinflammatory product of arachidonic acid metabolism that has been implicated as a mediator in a number of inflammatory diseases. When injected intradermally into the guinea pig, LTB4 elicits a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-p ropyl-2H-1-benzopyran-2-carboxylic acid), a first-generation LTB4 receptor antagonist inhibited the chemotactic actions of LTB4 when coadministered into the dermal site and when given orally with ED50 values of 340 ng and 1.7 mg/kg, respectively. The second-generation LTB4 receptor antagonists SC-50605 (7-[3-[2(cyclopropylmethyl)-3-methoxy-4-(4-thiazolyl)phenoxy]propoxy]- 3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid) and SC-51146 (7-[3-[2(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl] phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid) inhibited LTB4-induced chemotaxis when coadministered with ED50 values of 70 ng and 32 ng, respectively, and when given intragastrically with ED50 values of 0.10 and 0.09 mg/kg, respectively. SC-41930, SC-50605, and SC-51146 had oral durations of action of 5.5, 15, and 21 h, respectively. These potent, LTB4 receptor antagonists may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, where LTB4 is implicated as an inflammatory mediator.
Subject(s)
Benzamides/pharmacology , Benzopyrans/pharmacology , Chemotaxis, Leukocyte/drug effects , Leukotriene B4/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Skin/drug effects , Thiazoles/pharmacology , Administration, Oral , Animals , Benzamides/administration & dosage , Benzopyrans/administration & dosage , Granulocytes/drug effects , Guinea Pigs , Injections, Intradermal , Male , Peroxidase/analysis , Receptors, Leukotriene B4 , Skin/cytology , Thiazoles/administration & dosageABSTRACT
SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4- dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, is a selective, orally active, LTB4 receptor antagonist currently in clinical trials for psoriasis and ulcerative colitis. Exhaustive SAR studies found a potential backup compound, SC-50605, which was 7-16 times more potent than SC-41930 in LTB4 receptor binding, chemotaxis and degranulation assays. SC-50605 also inhibited LTB4-induced intradermal chemotaxis in cavine skin at an oral dose of 0.10 mg/kg and displayed good activity in animal models of colitis and epidermal inflammation both orally and topically.
Subject(s)
Benzopyrans/pharmacology , Colitis/drug therapy , Dermatitis/drug therapy , Leukotriene B4/antagonists & inhibitors , Thiazoles/pharmacology , Animals , Benzopyrans/administration & dosage , Benzopyrans/chemical synthesis , Benzopyrans/metabolism , Binding Sites , Cell Degranulation/drug effects , Chemotaxis, Leukocyte/drug effects , Disease Models, Animal , Drug Design , Guinea Pigs , In Vitro Techniques , Mice , Receptors, Leukotriene B4/metabolism , Thiazoles/administration & dosage , Thiazoles/chemical synthesis , Thiazoles/metabolismABSTRACT
Psoriasis is a disease state characterized by epidermal proliferation, neutrophil infiltration, along with release of the proinflammatory mediators leukotriene-B4 (LTB4) and 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE]. LTB4 and 12(R)-HETE are chemoattractant to the neutrophil, the latter approximately 1000X less potent. LTB4 and 12(R)-HETE are present in psoriatic scale, the latter in quantities so much greater than LTB4 that it is proposed as a primary mediator of neutrophil infiltration in psoriasis. 12(R)-HETE, synthesized in optically pure form by a new, shorter route, was injected into the cavine dermis. At a dose of 25 micrograms m per intradermal site, 12(R)-HETE was a significant chemoattractant to the neutrophil (as assessed by dermal myeloperoxidase levels). SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]- 3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, given intragastrically inhibited 12(R)-HETE-induced neutrophil infiltration of the cavine dermis with an ED50 value of 13.5 mg/kg. Compounds such as SC-41930 may well have utility for treating human psoriasis.
Subject(s)
Benzopyrans/pharmacology , Hydroxyeicosatetraenoic Acids/pharmacology , Neutrophils/drug effects , Skin/cytology , 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid , Animals , Chemotaxis, Leukocyte/drug effects , Guinea Pigs , In Vitro Techniques , Injections, Intradermal , Male , Peroxidase/analysis , Peroxidase/metabolism , Skin/drug effectsABSTRACT
Psoriasis is a disease state characterized by epidermal proliferation, neutrophil infiltration, along with release of the proinflammatory mediators leukotriene-B4(LTB4) and 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE]. LTB4 and 12(R)-HETE are chemoattractant to the neutrophil, the latter approximately 1000x less potent. LTB4 and 12(R)-HETE are present in psoriatic scale, the latter in quantities so much greater than LTB4 that it is proposed as a primary mediator of neutrophil infiltration in psoriasis. 12(R)-HETE, synthesized in optically pure form by a new, shorter route, was injected into the dermis of the cavine, lapine, canine, mouse and rat. At doses up to 50 mu gm per intradermal site, 12(R)-HETE was chemoattractant to the neutrophil (as assessed by dermal myeloperoxidase levels) with response in the cavine greater than canine greater than lapine greater than mouse greater than rat.
