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1.
Bioorg Med Chem ; 26(1): 200-214, 2018 01 01.
Article in English | MEDLINE | ID: mdl-29203142

ABSTRACT

A highly potent and well-balanced dual agonist for the EP2 and EP3 receptors is described. Optimization of the lead compound was accomplished in consideration of the relative agonist activity against each EP subtype receptor and the pharmacokinetic profile. As the result, 2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}eth-yl)thio]-1,3-thiazole-4-carboxylic acid (10) showed excellent potency (human EC50 EP2 = 1.1 nM, EP3 = 1.0 nM) with acceptable selectivity over the EP1 and EP4 subtypes (>2000-fold). Further fine-tuning of compound 10 led to identification of ONO-8055 as a clinical candidate. ONO-8055 was effective at an extremely low dose (0.01 mg/kg, po, bid) in rats, and dose-dependently improved voiding dysfunction in a monkey model of underactive bladder (UAB). ONO-8055 is expected to be a novel and highly promising drug for UAB.


Subject(s)
Receptors, Prostaglandin E, EP2 Subtype/agonists , Receptors, Prostaglandin E, EP3 Subtype/agonists , Thiazoles/pharmacology , Animals , Caco-2 Cells , Cell Membrane Permeability/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Haplorhini , Humans , Male , Models, Molecular , Molecular Structure , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry
2.
Bioorg Med Chem Lett ; 26(3): 1016-1019, 2016 Feb 01.
Article in English | MEDLINE | ID: mdl-26725951

ABSTRACT

The cyclic carbamate derivatives, 2-{[2-((4S)-4-{(1E,3R)-8-fluoro-3-hydroxy-4,4-dimethyl-1-octenyl}-2-oxo-1,3-oxazolidin-3-yl)ethyl]sulfanyl}-1,3-thiazole-4-carboxylic acid (5) and 2-{[2-((4S)-4-{(1E,3R)-3-[1-(4-fluorobutyl)cyclobutyl]-3-hydroxy-1-propenyl}-2-oxo-1,3-oxazolidin-3-yl)ethyl]sulfanyl}-1,3-thiazole-4-carboxylic acid (7) were identified as the first potent dual EP2 and EP3 agonists with selectivity against the EP1 and EP4 subtypes. Compounds 5 and 7 demonstrated highly potent dual EP2 and EP3 agonist activity with EC50 values of 10nM or less. In addition, these compounds possess structural features distinct from natural prostaglandins, such as a cyclic carbamate moiety, a dimethyl or cyclobutyl group and a terminal fluorine atom.


Subject(s)
Carboxylic Acids/chemistry , Receptors, Prostaglandin E, EP2 Subtype/agonists , Receptors, Prostaglandin E, EP3 Subtype/agonists , Animals , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacokinetics , Half-Life , Humans , Kinetics , Mice , Protein Binding , Rats , Receptors, Prostaglandin E, EP1 Subtype/agonists , Receptors, Prostaglandin E, EP1 Subtype/metabolism , Receptors, Prostaglandin E, EP2 Subtype/metabolism , Receptors, Prostaglandin E, EP3 Subtype/metabolism , Receptors, Prostaglandin E, EP4 Subtype/agonists , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Structure-Activity Relationship
3.
J Bone Miner Metab ; 34(1): 33-40, 2016 Jan.
Article in English | MEDLINE | ID: mdl-25762435

ABSTRACT

This study examined the effects of a novel cathepsin K inhibitor, ONO-KK1-300-01 (KK1-300), used concurrently with parathyroid hormone (PTH) in ovariectomized (OVX) rats. KK1-300 (3 mg/kg, twice daily), alendronate (1 mg/kg, once daily) or vehicle were orally administered to OVX rats for 56 days, starting the day after ovariectomy, followed by combination treatment with or without PTH (3 µg/kg, subcutaneously three times a week) for another 28 days. OVX control animals exhibited a significant increase in both bone resorption (urinary deoxypyridinoline; DPD) and formation markers (serum osteocalcin) as well as microstructural changes associated with decreased bone mineral density (BMD). Combination treatment with KK1-300 and PTH significantly decreased urinary DPD and increased serum osteocalcin, indicating a sustained beneficial effect compared to the effect of each mono-therapy. On the other hand, combination therapy with alendronate and PTH weakened the PTH-induced increase in osteocalcin. In proximal tibia, combination treatment with KK1-300 and PTH increased BMD to a level significantly higher than that achieved following single treatment with KK1-300 or PTH alone. On the other hand, combination treatment with alendronate and PTH failed to produce any significant additive effect on BMD following single treatment with alendronate or PTH alone. Microstructural analysis revealed that the PTH-induced increase in bone formation (MS/BS and BFR/BS) was fully maintained following combination treatment with KK1-300 and PTH, but not following combination treatment with alendronate and PTH. These findings indicate that KK1-300, unlike alendronate, has an additive effect on the preventive action of PTH on bone loss in OVX rats.


Subject(s)
Bone Density/drug effects , Cathepsin K/antagonists & inhibitors , Osteogenesis/drug effects , Ovariectomy , Parathyroid Hormone/pharmacology , Alendronate/pharmacology , Alendronate/therapeutic use , Animals , Bone Resorption/drug therapy , Female , Parathyroid Hormone/therapeutic use , Rats
4.
J Med Chem ; 58(15): 6093-113, 2015 Aug 13.
Article in English | MEDLINE | ID: mdl-26200813

ABSTRACT

An orally active dual CysLT1 and CysLT2 antagonist possessing a distinctive structure which consists of triple bond and dicarboxylic acid moieties is described. Gemilukast (ONO-6950) was generated via isomerization of the core indole and the incorporation of a triple bond into a lead compound. Gemilukast exhibited antagonist activities with IC50 values of 1.7 and 25 nM against human CysLT1 and human CysLT2, respectively, and potent efficacy at an oral dose of 0.1 mg/kg given 24 h before LTD4 challenge in a CysLT1-dependent guinea pig asthmatic model. In addition, gemilukast dose-dependently reduced LTC4-induced bronchoconstriction in both CysLT1- and CysLT2-dependent guinea pig asthmatic models, and it reduced antigen-induced constriction of isolated human bronchi. Gemilukast is currently being evaluated in phase II trials for the treatment of asthma.


Subject(s)
Asthma/drug therapy , Butyrates/pharmacology , Butyrates/therapeutic use , Indoles/pharmacology , Indoles/therapeutic use , Leukotriene Antagonists/pharmacology , Leukotriene Antagonists/therapeutic use , Receptors, Leukotriene/drug effects , Animals , Biological Availability , Dogs , Guinea Pigs , Humans , Leukotriene Antagonists/pharmacokinetics , Rats
5.
Neuropharmacology ; 99: 51-66, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26189762

ABSTRACT

Accumulating evidence has shown the pathophysiological significance of the translocator protein 18 kDa (TSPO) in the central nervous system. In this study, we evaluated the beneficial effects of ONO-2952, a novel TSPO antagonist in rat stress models. ONO-2952 potently bound both rat and human TSPO (Ki=0.330-9.30 nmol/L) with high selectivity over other receptors, transporters, ion channels and enzymes. ONO-2952 inhibited both neurosteroid accumulation and noradrenaline release in the brain of rats exposed to acute stress. The inhibitory effect of ONO-2952 on stress-induced noradrenaline release was attenuated by co-treatment with the TSPO agonist CB34 in a dose-dependent manner. ONO-2952, at 0.3 mg/kg or higher, dose-dependently suppressed restraint stress-induced defecation in rats with brain TSPO occupancy of more than 50%. In addition, ONO-2952, at 1 mg/kg or higher, suppressed conditioned fear stress-induced freezing behavior in rats with an efficacy equivalent to that of diazepam, given orally at 3 mg/kg. Results of the passive avoidance learning test revealed that ONO-2952, unlike diazepam, did not affect learning and memory even at doses 10 times higher than its effective doses in the stress models. The present findings indicate that ONO-2952 is a promising candidate for the treatment of stress-related disorders.


Subject(s)
Cyclopropanes/pharmacology , Heterocyclic Compounds, 4 or More Rings/pharmacology , Psychotropic Drugs/pharmacology , Stress, Psychological/drug therapy , Amygdala/drug effects , Amygdala/metabolism , Animals , Avoidance Learning/drug effects , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/metabolism , Cell Line, Tumor , Cyclopropanes/chemistry , Cyclopropanes/pharmacokinetics , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Freezing Reaction, Cataleptic/drug effects , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Hippocampus/drug effects , Hippocampus/metabolism , Humans , Male , Psychotropic Drugs/chemistry , Psychotropic Drugs/pharmacokinetics , Rats, Sprague-Dawley , Rats, Wistar , Receptors, GABA/metabolism , Receptors, GABA-A/metabolism , Restraint, Physical , Stress, Psychological/metabolism
6.
J Bone Miner Metab ; 32(6): 645-52, 2014 Nov.
Article in English | MEDLINE | ID: mdl-24317478

ABSTRACT

This study compared the effects of ONO-5334, a cathepsin K inhibitor, with those of alendronate on bone mass and strength in ovariectomized rats. Ovariectomy resulted in significant elevation in urinary deoxypyridinoline and plasma C-terminal cross-linking telopeptide of type I collagen (CTX) 8 weeks after surgery. Peripheral quantitative computed tomography analysis showed that total, trabecular, and cortical bone mineral content (BMC) decreased in the proximal tibia, which was paralleled with a significant decline in bone strength. Treatment with ONO-5334 (0.12, 0.6, 3 or 15 mg/kg) once daily for 8 weeks dose-dependently restored the decrease in total BMC and bone mineral density (BMD) in the proximal tibia and suppressed urinary deoxypyridinoline and plasma CTX levels. Alendronate (1 mg/kg, once daily) also fully restored these bone mass parameters. Separate analysis of trabecular and cortical bones, however, showed that ONO-5334 only partially restored trabecular BMD and BMC at 15 mg/kg, whereas alendronate fully restored these parameters. On the other hand, ONO-5334 increased both cortical BMD and BMC with an effect more potent than that of alendronate. Bone geometric analysis indicated that ONO-5334 at 15 mg/kg decreased endosteal circumference without affecting periosteal circumference, resulting in marked increase in cortical thickness. Interestingly, the effects of ONO-5334 on bone strength parameters were more prominent than those of alendronate, although the two test compounds had a similar effect on total BMC. Taken together, our results indicate that ONO-5334 has pharmacological characteristics different from those of alendronate and may offer a unique therapy for patients with osteoporosis.


Subject(s)
Bone Density/drug effects , Cathepsin K/antagonists & inhibitors , Osteoporosis/drug therapy , Thiazolidines/pharmacology , Tibia/metabolism , Alendronate/pharmacology , Animals , Bone Density Conservation Agents/pharmacology , Female , Osteoporosis/metabolism , Osteoporosis/pathology , Ovariectomy , Rats , Tibia/pathology
7.
J Org Chem ; 72(13): 4596-610, 2007 Jun 22.
Article in English | MEDLINE | ID: mdl-17511507

ABSTRACT

A first-generation strategy for construction of (+)-nodulisporic acids A (1) and B (2) is described. The strategy entails union of the eastern and western hemisphere subtargets via the indole synthesis protocol developed in our laboratory. Subsequent elaboration of rings E and F, however, revealed the considerable acid instability of the C(24) hydroxyl, thereby preventing further advancement. Nonetheless, preparation of the heptacyclic core of (+)-nodulisporic acids A and B, the total synthesis of (+)-nodulisporic acid F, the simplest member of the nodulisporic acid family, and elaboration of the heptacyclic core of (-)-nodulisporic acid D were achieved.


Subject(s)
Diterpenes/chemistry , Indoles/chemical synthesis , Aldehydes/chemistry , Alkylation , Aniline Compounds/chemistry , Benzyl Alcohol/chemistry , Benzyl Compounds/chemistry , Ethers/chemistry , Hydrazones/chemistry , Indoles/chemistry , Lactones/chemistry , Molecular Structure , Stereoisomerism , Toluidines/chemistry
8.
J Org Chem ; 72(13): 4611-20, 2007 Jun 22.
Article in English | MEDLINE | ID: mdl-17511508

ABSTRACT

A second-generation strategy for construction of (+)-nodulisporic acids A and B based on the development of a new, effective modular indole synthesis exploiting a sequential Stille cross-coupling/Buchwald-Hartwig union/cyclization tactic is disclosed. This strategy evolved due to the considerable acid instability of the C(24) hydroxyl group observed in several advanced intermediates during our first-generation approach.


Subject(s)
Diterpenes/chemical synthesis , Indoles/chemical synthesis , Amination , Aniline Compounds/chemistry , Crystallography, X-Ray , Cyclization , Diterpenes/chemistry , Indoles/chemistry , Kinetics , Lactones/chemistry , Models, Molecular , Molecular Structure , Thermodynamics
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