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1.
ACS Med Chem Lett ; 11(6): 1145-1151, 2020 Jun 11.
Article in English | MEDLINE | ID: mdl-32550994

ABSTRACT

A novel series of macrocyclic pyrazolo[1,5-a]pyrimidine derivatives as respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors were designed and synthesized based on docking studies of acyclic inhibitors. This effort resulted in the discovery of several macrocyclic compounds, such as 12b, 12f, and 12h, with low nanomolar to subnanomolar activities against the wild-type RSV F protein A2. In addition, 12h showed a single-digit nanomolar potency against the previously reported drug-resistant mutant D486N. Molecular modeling and computational analyses suggested that 12h binds to the D486N mutant while maintaining a rigid bioactive conformation via macrocyclization and that it interacts with a hydrophobic cavity of the mutant using a new interaction surface of 12h. This report describes the rational design of macrocyclic compounds with dual inhibitory activities against wild-type and mutant RSV F proteins.

2.
Chem Pharm Bull (Tokyo) ; 68(4): 345-362, 2020.
Article in English | MEDLINE | ID: mdl-32238652

ABSTRACT

Respiratory syncytial virus (RSV) is one of the most common causes of lower respiratory tract infections and a significant pathogen for both adults and children. Although two drugs have been approved for the treatment of RSV infections, the low therapeutic index of these drugs have led pharmaceutical companies to develop safe and effective small-molecule anti-RSV drugs. The pyrazolo[1,5-a]pyrimidine series of compounds containing a piperidine ring at the 2-position of the pyrazolo[1,5-a]pyrimidine scaffold are known as candidate RSV fusion (F) protein inhibitor drugs, such as presatovir and P3. The piperidine ring has been revealed to facilitate the formation of an appropriate dihedral angle between the pyrazolo[1,5-a]pyrimidine scaffold and the plane of the amide bond for exertion of anti-RSV activity. A molecular-dynamic study on newly designed compounds with an acyclic chain instead of the piperidine ring proposed and demonstrated a new series of pyrazolo[1,5-a]pyrimidine derivatives, such as 9c with a 1-methyaminopropyl moiety, showing similar dihedral angle distributions to those in presatovir. Compound 9c exhibited potent anti-RSV activity with an EC50 value of below 1 nM, which was similar to that of presatovir. A subsequent optimization study on the benzene ring of 9c led to the potent RSV F protein inhibitor 14f with an EC50 value of 0.15 nM. The possibility of improving the biological properties of anti-RSV agents by modification at the 7-position of pyrazolo[1,5-a]pyrimidine is also discussed.


Subject(s)
Antiviral Agents/pharmacology , Drug Design , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Respiratory Syncytial Virus, Human/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Humans , Microbial Sensitivity Tests , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Stereoisomerism , Structure-Activity Relationship
3.
Chem Pharm Bull (Tokyo) ; 64(3): 228-38, 2016.
Article in English | MEDLINE | ID: mdl-26936050

ABSTRACT

We previously reported 2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide 2 as on orally available monoacylglycerol acyltransferase 2 (MGAT2) inhibitor which exhibited an in vivo efficacy at an oral dose of 100 mg/kg in a mouse oral lipid tolerance test. Further optimization of compound 2 to improve the intrinsic potency culminated in the identification of compound 11. Compound 11 showed a >50-fold lower IC50 against human MGAT2 enzyme than 2. Oral administration of 11 at a dose of 3 mg/kg in the oral lipid tolerance test resulted in significant suppression of triglyceride synthesis.


Subject(s)
N-Acetylglucosaminyltransferases/antagonists & inhibitors , Tetrahydroisoquinolines/pharmacology , Administration, Oral , Humans , Structure-Activity Relationship , Tetrahydroisoquinolines/administration & dosage , Tetrahydroisoquinolines/chemistry
4.
Chem Pharm Bull (Tokyo) ; 61(5): 587-91, 2013.
Article in English | MEDLINE | ID: mdl-23649202

ABSTRACT

Deprotection of a methoxymethyl (MOM) group on an oxindole nitrogen under basic conditions is demonstrated. The mechanisms of both the deprotection and the formation of N-methyloxindole were revealed by using deuterated NaOMe-MeOH in mechanistic studies.


Subject(s)
Indoles/chemical synthesis , Spiro Compounds/chemistry , Indoles/chemistry , Molecular Conformation
5.
Org Lett ; 15(7): 1748-51, 2013 Apr 05.
Article in English | MEDLINE | ID: mdl-23530662

ABSTRACT

The biomimetic synthesis of the advanced model compound of chloropupukeananin has been achieved. The present synthesis features an unexpected enantiomer-differentiating Diels-Alder/carbonyl-ene cascade under high-pressure conditions and a base-promoted migration of the salicyl group.


Subject(s)
Sesquiterpenes/chemical synthesis , Biomimetics , Models, Molecular , Molecular Structure , Salicylates/chemistry , Sesquiterpenes/chemistry , Stereoisomerism
6.
Bioorg Med Chem ; 20(21): 6248-55, 2012 Nov 01.
Article in English | MEDLINE | ID: mdl-23026082

ABSTRACT

Doxorubicin, a commonly used cancer chemotherapy agent, elicits several potent biological effects, including synergistic-antitumor activity in combination with cisplatin. However, the mechanism of this synergism remains obscure. Here, we employed an improved T7 phage display screening method to identify Fanconi anemia group F protein (FANCF) as a doxorubicin-binding protein. The FANCF-doxorubicin interaction was confirmed by pull-down assay and SPR analysis. FANCF is a component of the Fanconi anemia complex, which monoubiquitinates D2 protein of Fanconi anemia group as a cellular response against DNA cross-linkers such as cisplatin. We observed that the monoubiquitination was inhibited by doxorubicin treatment.


Subject(s)
Antineoplastic Agents/pharmacology , Doxorubicin/pharmacology , Fanconi Anemia Complementation Group F Protein/antagonists & inhibitors , Antineoplastic Agents/chemistry , Binding Sites/drug effects , Doxorubicin/chemistry , Fanconi Anemia Complementation Group D2 Protein/antagonists & inhibitors , Fanconi Anemia Complementation Group D2 Protein/metabolism , Fanconi Anemia Complementation Group F Protein/chemistry , HEK293 Cells , Humans , Kinetics , Molecular Structure , Peptide Library , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Structure-Activity Relationship , Surface Plasmon Resonance
7.
Bioorg Med Chem ; 16(22): 9837-46, 2008 Nov 15.
Article in English | MEDLINE | ID: mdl-18930404

ABSTRACT

Here, we report an efficient one-cycle affinity selection using a natural-protein or random-peptide T7 phage pool for identification of binding proteins or peptides specific for small-molecules. The screening procedure involved a cuvette type 27-MHz quartz-crystal microbalance (QCM) apparatus with introduction of self-assembled monolayer (SAM) for a specific small-molecule immobilization on the gold electrode surface of a sensor chip. Using this apparatus, we attempted an affinity selection of proteins or peptides against synthetic ligand for FK506-binding protein (SLF) or irinotecan (Iri, CPT-11). An affinity selection using SLF-SAM and a natural-protein T7 phage pool successfully detected FK506-binding protein 12 (FKBP12)-displaying T7 phage after an interaction time of only 10 min. Extensive exploration of time-consuming wash and/or elution conditions together with several rounds of selection was not required. Furthermore, in the selection using a 15-mer random-peptide T7 phage pool and subsequent analysis utilizing receptor ligand contact (RELIC) software, a subset of SLF-selected peptides clearly pinpointed several amino-acid residues within the binding site of FKBP12. Likewise, a subset of Iri-selected peptides pinpointed part of the positive amino-acid region of residues from the Iri-binding site of the well-known direct targets, acetylcholinesterase (AChE) and carboxylesterase (CE). Our findings demonstrate the effectiveness of this method and general applicability for a wide range of small-molecules.


Subject(s)
Bacteriophage T7/genetics , Biosensing Techniques , Carrier Proteins/metabolism , Peptide Library , Peptides/metabolism , Amino Acid Sequence , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/metabolism , Bacteriophage T7/metabolism , Biosensing Techniques/instrumentation , Camptothecin/analogs & derivatives , Camptothecin/chemistry , Camptothecin/metabolism , Carrier Proteins/biosynthesis , Carrier Proteins/chemistry , Drug Evaluation, Preclinical , Electrodes , Gold/chemistry , Irinotecan , Ligands , Molecular Sequence Data , Peptides/chemistry , Protein Structure, Tertiary , Structure-Activity Relationship , Tacrolimus Binding Proteins/chemistry , Tacrolimus Binding Proteins/metabolism
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