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1.
J Med Chem ; 44(8): 1297-304, 2001 Apr 12.
Article in English | MEDLINE | ID: mdl-11312928

ABSTRACT

Potent human chymase inhibitors with high enzymatic selectivity and satisfactory metabolic stability were obtained by replacing the Val-Pro (P3-P2) dipeptide portion of the previously described inhibitor 1 with a nonpeptidic pyrimidinone skeleton. The potency of the novel compounds was further enhanced by the introduction of carbamoyl-substituted difluoromethylene ketone moieties. The most potent chymase inhibitor of the newly created series was 2u (Y-40018), which had a K(i) of 2.62 nM. Compound 2u possessed high selectivity for human chymase since it lacked significant activity toward other representative human proteolytic enzymes. Moreover its strict specificity for human chymase suggested that 2u strongly inhibited human and canine chymases but not rat and mouse ones. Pharmacokinetic studies in rats and dogs indicated that 2u was absorbed rapidly after oral administration and had satisfactory bioavailability in these experimental animal species (rat, 17%; dog, 32%). In conclusion, 2u is a novel, potent, and orally active chymase inhibitor which would prove very useful in revealing the precise roles of the latter in various pathophysiological processes.


Subject(s)
Ketones/chemical synthesis , Protease Inhibitors/chemical synthesis , Pyrimidinones/chemical synthesis , Serine Endopeptidases/metabolism , Animals , Biological Availability , Chymases , Dogs , Humans , Hydrolysis , Ketones/chemistry , Ketones/pharmacokinetics , Male , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Pyrimidinones/chemistry , Pyrimidinones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Serine Endopeptidases/chemistry , Structure-Activity Relationship
2.
J Med Chem ; 44(8): 1286-96, 2001 Apr 12.
Article in English | MEDLINE | ID: mdl-11312927

ABSTRACT

We designed nonpeptidic chymase inhibitors based on the structure of a peptidic compound (1) and demonstrated that the combination of a pyrimidinone skeleton as a P3-P2 scaffold and heterocycles as P1 carbonyl-activating groups can function as a nonpeptidic chymase inhibitor. In particular, introduction of heterobicycles such as benzoxazole resulted in more potent chymase-inhibitory activity. Detailed structure-activity relationship studies on the benzoxazole moiety and substituents at the 2-position of the pyrimidinone ring revealed that 2r (Y-40079) had the most potent chymase-inhibitory activity (K(i) = 4.85 nM). This compound was also effective toward chymases of nonhuman origin and showed good selectivity for chymases over other proteases. Pharmacokinetic studies in rats indicated that 2r was absorbed slowly after oral administration and showed satisfactory bioavailability (BA) (T(max) = 6.0 +/- 2.3 h, BA = 19.3 +/- 6.6%, t(1/2) = 35.7 +/- 13.3 h). In conclusion, 2r is a novel, potent, and orally active chymase inhibitor which would be a useful tool in elucidating the pathophysiological roles of chymase.


Subject(s)
Benzoxazoles/chemical synthesis , Protease Inhibitors/chemical synthesis , Pyrimidinones/chemical synthesis , Serine Endopeptidases/metabolism , Animals , Benzoxazoles/chemistry , Benzoxazoles/pharmacokinetics , Biological Availability , Chymases , Humans , Hydrolysis , In Vitro Techniques , Liver/metabolism , Male , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Pyrimidinones/chemistry , Pyrimidinones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Serine Endopeptidases/chemistry , Structure-Activity Relationship
3.
Bioorg Med Chem ; 9(2): 301-15, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11249123

ABSTRACT

Chymase possesses a wide variety of actions, including promotion of angiotensin II production and histamine release from mast cells. However, due to a lack of effective inhibitors featuring both high inhibitory activity and high metabolic stability, the pathophysiological role of chymase has not been fully elucidated. We designed non-peptidic inhibitors based on the predicted binding mode of the peptidic chymase inhibitor Val-Pro-Phe-CF3 and demonstrated that the Val-Pro unit is replaceable with a (5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)acetyl moiety. Structure-activity relationship studies revealed that phenyl substitution at the 2-position of the pyrimidinone ring is indispensable for high activity. The most potent compound 1h (Ki = 0.0506 microM) is superior in potency to the parent peptidic inhibitor Val-Pro-Phe-CF3 and has good selectivity for chymase over other proteases. The related analogue 1e was orally absorbed and maintained high plasma levels for at least 2h. These results suggest that the derivatives reported here could be developed as agents for treatment of chymase-induced disease.


Subject(s)
Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemical synthesis , Animals , Biological Availability , Cattle , Chymases , Combinatorial Chemistry Techniques , Humans , Ketones/chemical synthesis , Ketones/chemistry , Ketones/pharmacokinetics , Kinetics , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Rats , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokinetics , Structure-Activity Relationship
4.
J Med Chem ; 41(16): 2985-93, 1998 Jul 30.
Article in English | MEDLINE | ID: mdl-9685237

ABSTRACT

In continuation of our previous work on eosinophilia inhibitors, we synthesized an additional series of inhibitors, which consisted of 5-amino-1-[(methylamino)thiocarbonyl]-1H-1,2,4-triazole derivatives and a newly developed series of 1,2,4-triazolo[1,5-a]-1,3,5-triazine derivatives. We evaluated their inhibitory activity on the airway eosinophilia model, which was induced by the intravenous (iv) injection of Sephadex particles. In the 1,2,4-triazole series with various substituents at the 3 position of the triazole ring such as 2-furyl, pyridyl, and phenoxy, none of derivatives had comparable activity to the previously reported compound GCC-AP0341, 5-amino-3-(4-chlorophenyl)-1-[(methylamino)thiocarbonyl]-1H-1,2, 4-triazole. In the triazolo[1,5-a]triazine series, 2-(4-chlorophenyl)-6-methyl-1,2,4-triazolo[1,5-a]-1,3, 5-triazine-7(6H)-thione (3h) was highly potent, and when given orally it had an ID50 value of 0.3 mg/kg, which is comparable to that of GCC-AP0341. The fact that the structure-activity relationship of these two series was quite similar suggests that a common substructure, such as the 1,2,4-triazole ring with a substituted phenyl ring at the 3 position and a thiocarbonyl moiety at the 1 position, could contribute to the activity. Our selected compound 3h was less active than GCC-AP0341 in the antigen-induced hyper-responsiveness model in guinea pigs; however, we plan to carry out further studies on eosinophil functions, especially on their activation, using our two compounds, 3h and GCC-AP0341.


Subject(s)
Anti-Asthmatic Agents , Pulmonary Eosinophilia/prevention & control , Triazines , Triazoles , Animals , Anti-Asthmatic Agents/chemical synthesis , Anti-Asthmatic Agents/chemistry , Anti-Asthmatic Agents/pharmacology , Antigens, Helminth/immunology , Ascaris/immunology , Asthma/drug therapy , Asthma/immunology , Cell Count/drug effects , Dextrans/toxicity , Drug Evaluation, Preclinical , Eosinophils/cytology , Eosinophils/drug effects , Guinea Pigs , Humans , In Vitro Techniques , Male , Pulmonary Eosinophilia/chemically induced , Pulmonary Eosinophilia/immunology , Respiratory Hypersensitivity/drug therapy , Respiratory Hypersensitivity/immunology , Structure-Activity Relationship , Triazines/chemical synthesis , Triazines/chemistry , Triazines/pharmacology , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/pharmacology
6.
Bioorg Med Chem Lett ; 8(8): 919-24, 1998 Apr 21.
Article in English | MEDLINE | ID: mdl-9871512

ABSTRACT

Appropriate structural modification of the difluoromethylene ketone derivatives at both P3 and P' positions led us to the discovery of peptidyl human heart chymase inhibitor 12h which shows potent activity with Ki = 6 nM and high selectivity against closely related serine protease bovine alpha-chymotrypsin (chymotrypsin Ki = > 100 microM). Using the compound 12b, a docking study with human heart chymase was carried out to presume probable interactions.


Subject(s)
Ketones/chemical synthesis , Myocardium/enzymology , Oligopeptides/chemical synthesis , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemical synthesis , Animals , Cattle , Chymases , Chymotrypsin/antagonists & inhibitors , Glutamic Acid , Humans , Indicators and Reagents , Ketones/chemistry , Ketones/pharmacology , Kinetics , Molecular Conformation , Molecular Structure , Oligopeptides/chemistry , Oligopeptides/pharmacology , Rats , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Software , Structure-Activity Relationship
7.
J Med Chem ; 39(15): 3019-29, 1996 Jul 19.
Article in English | MEDLINE | ID: mdl-8709136

ABSTRACT

In order to develop novel antiasthmatic agents based on a new mechanism of action, a series of 3-substituted 5-amino-1-[(methylamino)(thiocarbonyl)]-1H-1,2,4-triazole derivatives were synthesized and evaluated in a model in which eosinophilia was induced in the airway through intravenous (iv) injection of Sephadex particles on days 0, 2, and 5. After screening of several hundred derivatives, we finally identified the highly potent eosinophilia inhibitor 5-amino-3-(4-chlorophenyl)-1-[(methylamino)(thiocarbonyl)]-1H-tria zole (23c, GCC-AP0341), which had ID50 values of 0.3 and 0.07 mg/kg when administered orally (os) and intraperitoneally (ip), respectively. This compound showed complete inhibition of the hypersensitivity induced by ascaris inhalation at an ip dose of 1 mg/kg as well as low toxicity, with an LD50 value of > 2.0 g/kg in mice. Extensive study of its mechanism of action revealed that 23c inhibited eosinophil survival induced by interleukin-5 (IL-5), but had little or no effect on leukotriene D4 (LTD4) or platelet-activating factor (PAF)-induced responses. Taken together, these results suggest 23c as a novel candidate for the treatment of chronic asthma. Further studies are now underway.


Subject(s)
Anti-Asthmatic Agents/chemical synthesis , Eosinophilia/drug therapy , Triazoles/chemical synthesis , Animals , Anti-Asthmatic Agents/pharmacology , Anti-Asthmatic Agents/therapeutic use , Antigens, Helminth/immunology , Ascaris/immunology , Cell Survival/drug effects , Dexamethasone/pharmacology , Dextrans , Eosinophils/drug effects , Guinea Pigs , Humans , Interleukin-5/pharmacology , Male , Molecular Structure , Pulmonary Eosinophilia/chemically induced , Pulmonary Eosinophilia/drug therapy , Rats , Rats, Wistar , Recombinant Proteins/pharmacology , Respiratory Hypersensitivity/drug therapy , Respiratory Hypersensitivity/immunology , Structure-Activity Relationship , Triazoles/pharmacology , Triazoles/therapeutic use
8.
J Med Chem ; 37(13): 1977-82, 1994 Jun 24.
Article in English | MEDLINE | ID: mdl-7913134

ABSTRACT

In order to develop novel compounds for topical use possessing antiallergic as well as antiinflammatory activities, a series of o-aminophenol derivatives bearing H1-antihistaminic structures were synthesized and their effects were investigated on lipid peroxidation in rat brain homogenates, antiinflammatory effection arachidonic acid- and 12-O-tetradecanoylphorbol-13- acetate-induced mouse ear edema and antiallergic effect on 48-h homologous passive cutaneous anaphylaxis in rats. Furthermore, the effects of these compounds on delayed-type hypersensitivity reaction in mice were examined. Several N-monosubstituted amino-4-methylphenols were found to exert potent inhibitory activities in all of these assays. Of these compounds, 4m was chosen for further development as AD0261.


Subject(s)
Aminophenols/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Histamine H1 Antagonists/pharmacology , Hypersensitivity, Delayed/drug therapy , Lipid Peroxidation/drug effects , Passive Cutaneous Anaphylaxis/drug effects , Administration, Topical , Aminophenols/administration & dosage , Aminophenols/chemical synthesis , Aminophenols/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antioxidants/chemical synthesis , Antioxidants/chemistry , Antioxidants/pharmacology , Arachidonic Acid/pharmacology , Brain/drug effects , Ear , Edema/drug therapy , Guinea Pigs , Histamine H1 Antagonists/administration & dosage , Histamine H1 Antagonists/chemical synthesis , Male , Mice , Mice, Inbred ICR , Rats , Rats, Sprague-Dawley , Skin Tests , Tetradecanoylphorbol Acetate/pharmacology
9.
Chem Pharm Bull (Tokyo) ; 39(9): 2323-32, 1991 Sep.
Article in English | MEDLINE | ID: mdl-1804546

ABSTRACT

A series of 2-[4-(thiazol-2-yl)phenyl]propionic acids substituted at various positions were prepared by the reaction of diethyl 2-methyl-2-(4-thiocarbamoylphenyl)malonates with alpha-bromoaldehyde diethyl acetals or alpha-haloketones followed by hydrolysis of esters. The inhibition of prostaglandin H synthetase (cyclooxygenase) was assayed by use of an enzyme preparation from guinea pig polymorphonuclear leukocytes. Examination of the structure-activity relationship of these compounds indicated that the substitution pattern with halogens at position 3 (R1) of the benzene ring and a methyl group in position 4 (R2) and/or 5 (R3) of the thiazole ring were favorable for inhibitory activity. The compounds bearing bulky alkyl or polar functional groups at the R2 position were weak inhibitors. The potent inhibitors of cyclooxygenase were tested for their ability to reduce carrageenin-induced inflammation of rat paws. These derivatives had strong anti-inflammatory activity based on their strong inhibition of cyclooxygenase, with some exceptions, including those with a thiomethyl group at R1.


Subject(s)
Cyclooxygenase Inhibitors/chemical synthesis , Phenylpropionates/chemical synthesis , Thiazoles/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase Inhibitors/pharmacology , Phenylpropionates/pharmacology , Rats , Rats, Inbred Strains , Structure-Activity Relationship , Thiazoles/pharmacology
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