ABSTRACT
We report the discovery of a series of novel zwitterionic hPTHR1 antagonists. Optimization of lead compound 2 led to 4-[[1-[4-(2,9-dichloro-5,5-dimethyl-6-oxo-pyrido[2,3-d][1]benzazepin-7-yl)phenyl]-3-fluoro-azetidin-3-yl]methylamino]cyclohexanecarboxylic acid (19e, DS69910557), a compound with excellent potency and selectivity over activity at the human ether-a-go-go-related-gene (hERG) channel. Compound 19e demonstrated in vivo potency to decrease the plasma calcium concentration in rats upon oral administration. 2022 Elsevier Ltd. All rights reserved.
Subject(s)
Benzazepines/pharmacology , Receptor, Parathyroid Hormone, Type 1 , Administration, Oral , Animals , Humans , Rats , Structure-Activity RelationshipABSTRACT
Structural modification of a 1,4-benzodiazepin-2-one-based PTHR1 antagonist 5, a novel type of PTHR1 antagonist previously synthesized in our laboratories, yielded compound 10, which had better chemical stability than compound 5. Successive optimization of the lead 10 improved aqueous solubility, metabolic stability, and animal pharmacokinetics, culminating in the identification of DS37571084 (12). Our study paves the way for the discovery of novel and orally bioavailable PTHR1 antagonists.
Subject(s)
Drug Discovery , Receptor, Parathyroid Hormone, Type 1/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Dose-Response Relationship, Drug , Humans , Male , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Rats , Rats, Sprague-Dawley , Receptor, Parathyroid Hormone, Type 1/metabolism , Structure-Activity RelationshipABSTRACT
The discovery and optimization of a novel series of PTHR1 antagonists are described. Starting from known PTHR1 antagonists, we identified more potent 1,4-benzodiazepin-2-one derivatives by means of a scaffold-hopping approach. The representative compound 23 (DS08210767) exhibited nanomolar-level PTHR1 antagonist activity and potential oral bioavailability in a pharmacokinetic study.
Subject(s)
Benzodiazepinones/pharmacology , Drug Discovery , Receptor, Parathyroid Hormone, Type 1/antagonists & inhibitors , Benzodiazepinones/chemical synthesis , Benzodiazepinones/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Receptor, Parathyroid Hormone, Type 1/metabolism , Structure-Activity RelationshipABSTRACT
Novel compounds based on 1a were synthesized with the focus of obtaining agonists acting upon peripheral BRS-3. To identify potent anti-obesity compounds without adverse effects on the central nervous system (CNS), a carboxylic acid moiety and a labile carboxylic ester with an antedrug functionality were introduced. Through the extensive synthetic exploration and the pharmacokinetic studies of intravenous administration in mice, the ester 2b was selected owing to its most suitable pharmacological profile. In the evaluation of food intake suppression in C57BL/6N mice, 2b showed significant in vivo efficacy and no clear adverse effects on blood pressure change in dogs administered the compound by intravenous infusion.
Subject(s)
Acetates/chemistry , Anti-Obesity Agents/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemistry , Imidazoles/chemistry , Receptors, Bombesin/agonists , Acetates/metabolism , Acetates/pharmacology , Animals , Anti-Obesity Agents/metabolism , Anti-Obesity Agents/pharmacology , Blood Pressure/drug effects , Brain/drug effects , Brain/metabolism , Central Nervous System/drug effects , Central Nervous System/metabolism , Dogs , Eating/drug effects , Half-Life , Heart Rate/drug effects , Heterocyclic Compounds, 2-Ring/metabolism , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Injections, Intravenous , Mice , Mice, Inbred C57BL , Receptors, Bombesin/metabolismABSTRACT
Expansion of the 6-membered ring and subsequent fine-tuning of the newly obtained 7-membered spiropiperidine structure resulted in the discovery of a series of novel and potent SCD1 inhibitors. Preliminary SAR was explored by modifying an alkyl chain on the azepine nitrogen and resulted in the identification of a highly potent SCD1 inhibitor: 6-[5-(cyclopropylmethyl)-4,5-dihydro-1'H,3H-spiro[1,5-benzoxazepine-2,4'-piperidin]-1'-yl]-N-(2-hydroxy-2-pyridin-3-ylethyl)pyridazine-3-carboxamide (9). Compound 9 exhibited an IC(50) value of 0.01 µM against human SCD1.
Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , Piperidines/pharmacology , Spiro Compounds/pharmacology , Stearoyl-CoA Desaturase/antagonists & inhibitors , Animals , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , HEK293 Cells , Humans , Mice , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Stearoyl-CoA Desaturase/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In continuation of our investigation on novel stearoyl-CoA desaturase (SCD) 1 inhibitors, we have already reported on the structural modification of the benzoylpiperidines that led to a series of novel and highly potent spiropiperidine-based SCD1 inhibitors. In this report, we would like to extend the scope of our previous investigation and disclose details of the synthesis, SAR, ADME, PK, and pharmacological evaluation of the spiropiperidines with high potency for SCD1 inhibition. Our current efforts have culminated in the identification of 5-fluoro-1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4'-piperidine] (10e), which demonstrated a very strong potency for liver SCD1 inhibition (ID(50)=0.6 mg/kg). This highly efficacious inhibition is presumed to be the result of a combination of strong enzymatic inhibitory activity (IC(50) (mouse)=2 nM) and good oral bioavailability (F >95%). Pharmacological evaluation of 10e has demonstrated potent, dose-dependent reduction of the plasma desaturation index in C57BL/6J mice on a high carbohydrate diet after a 7-day oral administration (q.d.). In addition, it did not cause any noticeable skin abnormalities up to the highest dose (10 mg/kg).
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Stearoyl-CoA Desaturase/antagonists & inhibitors , Animals , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred C57BL , Pyridines/chemistry , Pyridines/pharmacokinetics , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
High S(N)2' selectivity in the allylic substitution of cyclohexylidene ethyl picolinates with copper reagents prepared from RMgBr and CuBr.Me(2)S was realized by addition of ZnX(2) (X = I, Br, Cl). Furthermore, ZnX(2) accelerated the reaction with the bulky iPr reagent.
Subject(s)
Cyclohexanes/chemistry , Carbon/chemistry , Copper/chemistry , Picolinic Acids/chemistryABSTRACT
Starting from a known piperazine-based SCD-1 inhibitor, we obtained more potent benzoylpiperidine analogs. Optimization of the structure of the benzoylpiperidine-based SCD-1 inhibitors resulted in the identification of 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-yl-ethyl)amide (24) which showed strong inhibitory activity against both human and murine SCD-1. In addition, this compound exhibited good oral bioavailability and demonstrated plasma triglyceride lowering effects in Zucker fatty rats in a dose-dependent manner after a 7-day oral administration (qd).
Subject(s)
Enzyme Inhibitors/chemistry , Hypoglycemic Agents/chemistry , Piperidines/chemistry , Pyridazines/chemistry , Pyridines/chemistry , Stearoyl-CoA Desaturase/antagonists & inhibitors , Triglycerides/blood , Administration, Oral , Animals , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Mice , Microsomes, Liver/metabolism , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Rats , Rats, Zucker , Stearoyl-CoA Desaturase/metabolismABSTRACT
Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3mg/kg) in our preliminary analysis.
Subject(s)
Benzopyrans/chemical synthesis , Piperidines/chemical synthesis , Stearoyl-CoA Desaturase/antagonists & inhibitors , Administration, Oral , Animals , Benzopyrans/chemistry , Benzopyrans/pharmacokinetics , Cell Line, Tumor , Humans , Mice , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Piperidines/chemistry , Piperidines/pharmacokinetics , Stearoyl-CoA Desaturase/metabolismABSTRACT
To establish allylic substitution of secondary allylic alcohol derivatives with alkynyl copper reagents, allylic esters bearing the (2-pyridine)CO2-, (2-pyrazine)CO2-, (EtO)2PO2-, C6F5CO2-, o-(Ph2P)C6H4CO2-, MeOCO2-, or AcO- group were examined. First, picolinate (R1 = Me, R2 = CH2OPMB) was subjected to reaction with (TMS-C[triple bond]C)2CuLi.LiBr at 0degreesC. Although no substitution took place, MgBr2 (3 equiv) was found to promote the reaction to produce the anti SN2' product in 93% yield with 94% regioselectivity and 99% chirality transfer. In contrast, substitution of the other esters with the copper reagent in the presence of MgBr2 were less reactive ((2-pyrazine)CO2-) or marginally reactive (other cases). Generality of the substitution using picolinates was established with five picolinates (R1 = Me, Ph(CH2)2, PMBO(CH2)3; R2 = Me, CH2OPMB, CH2OTBS, C5H11, c-C6H11) and seven alkynyl copper reagents (R3 = TMS, Ph, p-TBSOC6H4, p- and o-MeOC6H4, p-MeC6H4, p-FC6H4), furnishing anti SN2' products in 61-93% yields with high regioselectivity (usually >90%) and high chirality transfer (usually >95%). In addition, transformation of the products was briefly studied.
Subject(s)
Alkynes/chemistry , Alkynes/chemical synthesis , Allyl Compounds/chemistry , Copper/chemistry , Organometallic Compounds/chemistry , Picolinic Acids/chemistry , Molecular Structure , StereoisomerismABSTRACT
A series of structurally novel stearoyl-CoA desaturase-1 (SCD-1) inhibitors has been identified by optimizing a hit from our corporate library. Preliminary structure-activity relationship (SAR) studies led to the discovery of the highly potent and orally bioavailable thiazole-based SCD-1 inhibitor, 3-(2-hydroxyethoxy)-4-methoxy-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (23a).
Subject(s)
Benzamides/chemical synthesis , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Stearoyl-CoA Desaturase/antagonists & inhibitors , Thiazoles/chemical synthesis , Administration, Oral , Animals , Area Under Curve , Benzamides/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Mice , Mice, Inbred C57BL , Models, Chemical , Stearoyl-CoA Desaturase/chemistry , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
The continuing investigation of SAR studies of 3-(2-hydroxyethoxy)-N-(5-benzylthiazol-2-yl)-benzamides as stearoyl-CoA desaturase-1 (SCD-1) inhibitors is reported. Our prior hit-to-lead effort resulted in the identification of 1a as a potent and orally efficacious SCD-1 inhibitor. Further optimization of the structural motif resulted in the identification of 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (37c) with sub nano molar IC(50) in both murine and human SCD-1 inhibitory assays. This compound demonstrated a dose-dependent decrease in the plasma desaturation index in C57BL/6J mice on a non-fat diet after 7 days of oral administration.
Subject(s)
Benzamides/chemical synthesis , Chemistry, Pharmaceutical/methods , Stearoyl-CoA Desaturase/antagonists & inhibitors , Thiazoles/chemical synthesis , Administration, Oral , Animals , Area Under Curve , Benzamides/pharmacology , Dose-Response Relationship, Drug , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Mice , Mice, Inbred C57BL , Models, Chemical , Stearoyl-CoA Desaturase/chemistry , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
Allylic substitution with sp(2)-carbon reagents (aryl and alkenyl anions) was realized by using allylic picolinates and copper reagents derived from RMgBr and CuBr x Me(2)S to afford anti S(N)2' products regio- and stereoselectively. Steric and electronic factors in the reagents and the size of the methylene substituents around the allylic moiety marginally affected the selectivity. The reaction system was compatible with alkyl reagents as well. Furthermore, the substitution was applied to construction of a quaternary center and synthesis of (-)-sesquichamaenol. Electron-withdrawing nature of the pyridyl group and chelation of the C(=O)-C(5)H(4)N to MgBr(2) generated in situ were found to be responsible for the high efficiency of the substitution.
Subject(s)
Alkenes/chemical synthesis , Allyl Compounds/chemistry , Copper/chemistry , Organometallic Compounds/chemistry , Alkenes/chemistry , Molecular Structure , StereoisomerismABSTRACT
High regioselectivity for allylic substitution of the cyclopentenyl picolinate 5 with benzylcopper reagent was attained with ZnBr(2), and the finding was applied to the p-BrC(6)H(4)CH(2) reagent. The cyclopentene moiety in the product was reduced to the cyclopentane, and the p-BrC(6)H(4) was converted to the "Cu"C(6)H(4) for the second allylic substitution with picolinate 8 to furnish the title compound after oxidative cleavage of the resulting olefin moiety.
Subject(s)
Allyl Compounds/chemistry , Cyclopentanes/chemical synthesis , Phenylpropionates/chemical synthesis , Catalysis , Cyclopentanes/chemistry , Molecular Structure , Oxidation-Reduction , Phenylpropionates/chemistry , Phenylpropionates/pharmacology , Picolinic Acids/chemistryABSTRACT
The picolinoxy group was found to be an extremely powerful leaving group for allylic substitution with aryl nucleophiles derived from ArMgBr and CuBr*Me2S. The substitution proceeds with anti SN2' pathway and with high chirality transfer. The electron-withdrawing effect of the pyridyl group and chelation to MgBr2 are likely the origin of success. Results suggesting these effects were obtained.
Subject(s)
Allyl Compounds/chemical synthesis , Picolinic Acids/chemistry , Piperidines/chemistry , Allyl Compounds/chemistry , Anions , Indicators and Reagents/chemical synthesis , Indicators and Reagents/chemistry , Molecular Structure , StereoisomerismABSTRACT
Anti-SN2' mode of allylation of the monoester of 4-cyclopentene-1,3-diol with aryl and alkenyl anions was achieved, for the first time, with the MeOCH2CO2- group as a leaving group to which R-ZnBr and CuCl (as a catalyst) were best fitted. The aryl groups successfully installed were Ph, o- and p-MeC6H4, o-MOMOC6H4, o-MeOC6H4, and p-F-C6H4, while cis and trans alkenyl groups were attached with retention of the olefinic stereochemistries.
