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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.
Bioorg Med Chem Lett ; 29(11): 1380-1385, 2019 06 01.
Article in English | MEDLINE | ID: mdl-30952592

ABSTRACT

The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to a highly potent, selective and bioavailable DGAT1 inhibitor with the potential for further development.


Subject(s)
Benzimidazoles/pharmacology , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Chemistry, Pharmaceutical , Diacylglycerol O-Acyltransferase/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 29(10): 1182-1186, 2019 05 15.
Article in English | MEDLINE | ID: mdl-30926247

ABSTRACT

Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety. Our results show that single isomer 3A maintains in vitro and in vivo inhibition against DGAT1. In contrast to previous lead compounds, 3A does not undergo isomerization during in vitro hepatocyte incubation study or in vivo mouse study.


Subject(s)
Benzimidazoles/chemistry , Carboxylic Acids/chemistry , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Animals , Benzimidazoles/metabolism , Carboxylic Acids/metabolism , Chromatography, High Pressure Liquid , Cyclohexanones/chemistry , Diacylglycerol O-Acyltransferase/metabolism , Enzyme Inhibitors/analysis , Enzyme Inhibitors/metabolism , Hepatocytes/chemistry , Hepatocytes/metabolism , Humans , Inhibitory Concentration 50 , Isomerism , Mass Spectrometry , Mice , Rats
4.
Nucleosides Nucleotides Nucleic Acids ; 35(6): 277-94, 2016 Jun 02.
Article in English | MEDLINE | ID: mdl-27104963

ABSTRACT

Novel 2'-modified guanosine nucleosides were synthesized from inexpensive starting materials in 7-10 steps via hydroazidation or hydrocyanation reactions of the corresponding 2'-olefin. The antiviral effectiveness of the guanosine nucleosides was evaluated by converting them to the corresponding 5'-O-triphosphates (compounds 38-44) and testing their biochemical inhibitory activity against the wild-type NS5B polymerase.


Subject(s)
Antiviral Agents/chemical synthesis , Guanine Nucleotides/chemical synthesis , Nucleic Acid Synthesis Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Alkenes/chemical synthesis , Azides/chemical synthesis , Hepacivirus/enzymology , Viral Nonstructural Proteins/chemistry
5.
Bioorg Med Chem Lett ; 26(6): 1529-1535, 2016 Mar 15.
Article in English | MEDLINE | ID: mdl-26898814

ABSTRACT

MK-4256, a tetrahydro-ß-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-ß-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.


Subject(s)
Carbolines/chemistry , Carbolines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Animals , Carbolines/chemical synthesis , Dogs , Dose-Response Relationship, Drug , Humans , Mice , Molecular Structure , Rats , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 25(17): 3520-5, 2015 Sep 01.
Article in English | MEDLINE | ID: mdl-26199120

ABSTRACT

We report SAR studies on a novel non-peptidic somatostatin receptor 3 (SSTR3) agonist lead series derived from (4-phenyl-1H-imidazol-2-yl)methanamine. This effort led to the discovery of a highly potent low molecular weight SSTR3 agonist 5c (EC50=5.2 nM, MW=359). The results from molecular overlays of 5c onto the L-129 structure indicate good alignment, and two main differences of the proposed overlays of the antagonist MK-4256 onto the conformation of 5c lead to inversion of antagonism to agonism.


Subject(s)
Methylamines/chemistry , Receptors, Somatostatin/chemistry , Drug Discovery , Humans , Structure-Activity Relationship
7.
ACS Med Chem Lett ; 6(5): 513-7, 2015 May 14.
Article in English | MEDLINE | ID: mdl-26005524

ABSTRACT

The imidazolyl-tetrahydro-ß-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-ß-carboline (17e, MK-1421).

8.
ACS Med Chem Lett ; 5(10): 1082-7, 2014 Oct 09.
Article in English | MEDLINE | ID: mdl-25349648

ABSTRACT

We report the discovery of a novel series of DGAT1 inhibitors in the benzimidazole class with a piperdinyl-oxy-cyclohexanecarboxylic acid moiety. This novel series possesses significantly improved selectivity against the A2A receptor, no ACAT1 off-target activity at 10 µM, and higher aqueous solubility and free fraction in plasma as compared to the previously reported pyridyl-oxy-cyclohexanecarboxylic acid series. In particular, 5B was shown to possess an excellent selectivity profile by screening it against a panel of more than 100 biological targets. Compound 5B significantly reduces lipid excursion in LTT in mouse and rat, demonstrates DGAT1 mediated reduction of food intake and body weight in mice, is negative in a 3-strain Ames test, and appears to distribute preferentially in the liver and the intestine in mice. We believe this lead series possesses significant potential to identify optimized compounds for clinical development.

9.
ACS Med Chem Lett ; 5(7): 748-53, 2014 Jul 10.
Article in English | MEDLINE | ID: mdl-25050159

ABSTRACT

Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress.

10.
ACS Med Chem Lett ; 5(6): 690-5, 2014 Jun 12.
Article in English | MEDLINE | ID: mdl-24944745

ABSTRACT

A novel class of small-molecule, highly potent, and subtype-selective somatostatin SST3 agonists was discovered through modification of a SST3 antagonist. As an example, (1R,2S)-9 demonstrated not only potent in vitro SST3 agonist activity but also in vivo SST3 agonist activity in a mouse oral glucose tolerance test (OGTT). These agonists may be useful reagents for studying the physiological roles of the SST3 receptor and may potentially be useful as therapeutic agents.

11.
ACS Med Chem Lett ; 5(6): 717-21, 2014 Jun 12.
Article in English | MEDLINE | ID: mdl-24944750

ABSTRACT

We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.

12.
ACS Med Chem Lett ; 4(6): 509-13, 2013 Jun 13.
Article in English | MEDLINE | ID: mdl-24900701

ABSTRACT

We report herein the discovery of a fatty acid amide hydrolase (FAAH) positron emission tomography (PET) tracer. Starting from a pyrazole lead, medicinal chemistry efforts directed toward reducing lipophilicity led to the synthesis of a series of imidazole analogues. Compound 6 was chosen for further profiling due to its appropriate physical chemical properties and excellent FAAH inhibition potency across species. [(11)C]-6 (MK-3168) exhibited good brain uptake and FAAH-specific signal in rhesus monkeys and is a suitable PET tracer for imaging FAAH in the brain.

13.
ACS Med Chem Lett ; 4(8): 773-8, 2013 Aug 08.
Article in English | MEDLINE | ID: mdl-24900745

ABSTRACT

We report the design and synthesis of a series of novel DGAT1 inhibitors in the benzimidazole class with a pyridyl-oxy-cyclohexanecarboxylic acid moiety. In particular, compound 11A is a potent DGAT1 inhibitor with excellent selectivity against ACAT1. Compound 11A significantly reduces triglyceride excursion in lipid tolerance tests (LTT) in both mice and dogs at low plasma exposure. An in vivo study in mice with des-fluoro analogue 10A indicates that this series of compounds appears to distribute in intestine preferentially over plasma. The propensity to target intestine over plasma could be advantageous in reducing potential side effects since lower circulating levels of drug are required for efficacy. However, in the preclinical species, compound 11A undergoes cis/trans epimerization in vivo, which could complicate further development due to the presence of an active metabolite.

14.
ACS Med Chem Lett ; 3(6): 484-9, 2012 Jun 14.
Article in English | MEDLINE | ID: mdl-24900499

ABSTRACT

A structure-activity relationship study of the imidazolyl-ß-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice.

15.
16.
Bioorg Med Chem Lett ; 20(22): 6524-32, 2010 Nov 15.
Article in English | MEDLINE | ID: mdl-20933410

ABSTRACT

We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models.


Subject(s)
Obesity/drug therapy , Receptor, Melanocortin, Type 4/agonists , Triazoles/pharmacology , Animals , Chromatography, High Pressure Liquid , Disease Models, Animal , Mice , Mice, Knockout , Molecular Structure , Rats , Receptor, Melanocortin, Type 4/genetics , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/therapeutic use
19.
Bioorg Med Chem Lett ; 20(15): 4399-405, 2010 Aug 01.
Article in English | MEDLINE | ID: mdl-20598882

ABSTRACT

We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.


Subject(s)
Amides/chemistry , Anti-Obesity Agents/chemistry , Obesity/drug therapy , Pyrrolidines/chemistry , Receptor, Melanocortin, Type 4/agonists , Spiro Compounds/chemistry , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/therapeutic use , Body Weight/drug effects , Humans , Mice , Mice, Knockout , Pyrrolidines/pharmacokinetics , Pyrrolidines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/pharmacokinetics , Spiro Compounds/therapeutic use , Structure-Activity Relationship
20.
Bioorg Med Chem Lett ; 20(7): 2106-10, 2010 Apr 01.
Article in English | MEDLINE | ID: mdl-20207541

ABSTRACT

We report the design, synthesis and properties of spiroindane based compound 1, a potent, selective, orally bioavailable, non-peptide melanocortin subtype-4 receptor agonist. Compound 1 shows excellent erectogenic activity in the rodent models.


Subject(s)
Erectile Dysfunction/drug therapy , Indans/chemistry , Indans/therapeutic use , Receptor, Melanocortin, Type 4/agonists , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/chemistry , Spiro Compounds/therapeutic use , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Haplorhini , Humans , Indans/pharmacokinetics , Indans/pharmacology , Male , Mice , Molecular Structure , Protein Binding , Rats , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity Relationship
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