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1.
ACS Med Chem Lett ; 13(4): 734-741, 2022 Apr 14.
Article in English | MEDLINE | ID: mdl-35450359

ABSTRACT

Mutant isocitrate dehydrogenase 1 (IDH1) has been identified as an attractive oncology target for which >70% of grade II and III gliomas and ∼10% of acute myeloid leukemia (AML) harbor somatic IDH1 mutations. These mutations confer a neomorphic gain of function, leading to the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). We identified and developed a potent, selective, and orally bioavailable brain-penetrant tricyclic diazepine scaffold that inhibits mutant IDH1. During the course of in vitro metabolism studies, GSH-adduct metabolites were observed. The hypothesis for GSH-adduct formation was driven by the electron-rich nature of the tricyclic core. Herein, we describe our efforts to reduce the electron-rich nature of the core. Ultimately, a strategy focused on core modifications to block metabolic hot spots coupled with substitution pattern changes (C8 N → C linked) led to the identification of new tricyclic analogues with minimal GSH-adduct formation across species while maintaining an overall balanced profile.

2.
ACS Med Chem Lett ; 9(7): 679-684, 2018 Jul 12.
Article in English | MEDLINE | ID: mdl-30034600

ABSTRACT

A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.

3.
Bioorg Med Chem Lett ; 22(9): 3291-5, 2012 May 01.
Article in English | MEDLINE | ID: mdl-22465636

ABSTRACT

The introduction of A ring pyrazole modification to the hydrocortisone C-21 heteroaryl thioethers generated compounds with excellent transrepression potency (IL-8 inhibition) compared to their hydrocortisone analogs. However, the transcriptional transactivation activity of these compounds were considerably higher than the corresponding hydrocortisone analogs. Among all the compounds evaluated, a quinoxaline thioether modification demonstrated the best overall in vitro separation.


Subject(s)
Receptors, Glucocorticoid/drug effects , Steroids/chemistry , Sulfides/chemistry , Humans , Hydrocortisone , Pyrazoles/chemistry , Structure-Activity Relationship , Sulfides/pharmacology , Transcriptional Activation/drug effects
4.
Bioorg Med Chem Lett ; 22(2): 1086-90, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-22197391

ABSTRACT

The prednisolone C-21 heteroaryl thioethers have been synthesized and evaluated in cell based transrepression and transactivation assays. Most of the compounds demonstrated weak transactivational activity in both human and rat tyrosineaminotransferase functional assay while keeping potent anti-inflammatory activity. The benzimidazole thioether 7 exhibited comparable anti-inflammatory activity and improved safety profile compared to the classical oral steroid prednisolone.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Drug Discovery , Receptors, Glucocorticoid/agonists , Sulfides/pharmacology , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Biological Availability , Cell Line , Dose-Response Relationship, Drug , Hep G2 Cells , Humans , Molecular Conformation , Rats , Rats, Inbred BN , Receptors, Glucocorticoid/metabolism , Stereoisomerism , Structure-Activity Relationship , Sulfides/administration & dosage , Sulfides/chemistry , Tyrosine Transaminase/metabolism
5.
Bioorg Med Chem Lett ; 21(21): 6343-7, 2011 Nov 01.
Article in English | MEDLINE | ID: mdl-21944381

ABSTRACT

A series of C-21 mercapto derivatives of hydrocortisone have been synthesized and evaluated in cell based transrepression and transactivation assays. The benzothiazole derivative, compound 6 not only showed a dissociated profile in vitro functional assays but also a pharmacological profile in a Brown-Norway rat therapeutic index model of asthma that dissociated side effects (thymolysis) while maintaining efficacy against pulmonary inflammation and lung function.


Subject(s)
Steroids/pharmacology , Sulfhydryl Compounds/chemistry , Administration, Inhalation , Animals , Asthma/drug therapy , Cell Line , Drug Discovery , Lung/drug effects , Rats , Steroids/administration & dosage , Steroids/chemistry , Steroids/therapeutic use , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 18(1): 228-31, 2008 Jan 01.
Article in English | MEDLINE | ID: mdl-18006311

ABSTRACT

A series of novel and potent 3,4-diamino-2,5-thiadiazole-1-oxides were prepared and found to show excellent binding affinities for CXCR2 and CXCR1 receptors and excellent inhibitory activity of Gro-alpha and IL-8 mediated in vitro hPMN MPO release of CXCR2 and CXCR1 expressing cell lines. On the other hand, a closely related 3,4-diamino-2,5-thiadiazole-dioxide did not show functional activity despite its excellent binding affinities for CXCR2 and CXCR1 in membrane binding assays. A detailed SAR has been discussed in these two closely related structures.


Subject(s)
Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Animals , Chemokine CXCL1/chemistry , Chemokine CXCL1/pharmacology , Chemotactic Factors/chemistry , Chemotactic Factors/pharmacology , Humans , Interleukin-8/chemistry , Interleukin-8/pharmacology , Kinetics , Neutrophils/drug effects , Neutrophils/enzymology , Oxides/chemical synthesis , Oxides/chemistry , Oxides/pharmacokinetics , Oxides/pharmacology , Peroxidase/metabolism , Rats , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistry , Thiadiazoles/pharmacokinetics , Thiadiazoles/pharmacology
10.
J Med Chem ; 49(26): 7603-6, 2006 Dec 28.
Article in English | MEDLINE | ID: mdl-17181143

ABSTRACT

Structure-activity studies on lead cyclobutenedione 3 led to the discovery of 4 (SCH 527123), a potent, orally bioavailable CXCR2/CXCR1 receptor antagonist with excellent cell-based activity. Compound 4 displayed good oral bioavailability in rat and may be a potential therapeutic agent for the treatment of various inflammatory diseases.


Subject(s)
Benzamides/pharmacology , Cyclobutanes/pharmacology , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Animals , Benzamides/administration & dosage , Benzamides/chemical synthesis , Biological Availability , Cyclobutanes/administration & dosage , Cyclobutanes/chemical synthesis , Molecular Structure , Rats , Receptors, Interleukin-8A/metabolism , Receptors, Interleukin-8B/metabolism , Structure-Activity Relationship
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