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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.
J Med Chem ; 65(8): 6001-6016, 2022 04 28.
Article in English | MEDLINE | ID: mdl-35239336

ABSTRACT

3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology.


Subject(s)
Enzyme Inhibitors , Ethers, Cyclic , Amides , Cyclization , Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
3.
J Med Chem ; 64(7): 3911-3939, 2021 04 08.
Article in English | MEDLINE | ID: mdl-33755451

ABSTRACT

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising in vivo activity, and low human dose projections.


Subject(s)
Aminoquinolines/therapeutic use , Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Neoplasms/drug therapy , Nucleosides/therapeutic use , Protein-Arginine N-Methyltransferases/antagonists & inhibitors , Aminoquinolines/chemical synthesis , Aminoquinolines/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Cell Proliferation/drug effects , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Female , Humans , Mice, SCID , Molecular Docking Simulation , Molecular Structure , Nucleosides/chemical synthesis , Nucleosides/metabolism , Protein Binding , Protein-Arginine N-Methyltransferases/metabolism , Structure-Activity Relationship
4.
Bioorg Med Chem Lett ; 27(12): 2721-2726, 2017 06 15.
Article in English | MEDLINE | ID: mdl-28501511

ABSTRACT

Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.


Subject(s)
Inflammation/drug therapy , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Administration, Oral , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , High-Throughput Screening Assays , Imidazoles/pharmacology , Inflammation/enzymology , Interleukin-1 Receptor-Associated Kinases/metabolism , Interleukin-6/antagonists & inhibitors , Interleukin-6/biosynthesis , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Quinazolines/administration & dosage , Quinazolines/chemistry , Rats , Rats, Inbred Lew , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 26(11): 2735-8, 2016 06 01.
Article in English | MEDLINE | ID: mdl-27080185

ABSTRACT

Led by the structural information of the screening hit with mDM2 protein, a structure modification of Leu26 moiety of the novel p53-hDM2 inhibitors was conducted. A structure-activity relationship study of 4-substituted piperidines revealed compound 20t with good potencies and excellent CYP450 profiles.


Subject(s)
Leucine/chemistry , Piperidines/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Tumor Suppressor Protein p53/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Proto-Oncogene Proteins c-mdm2/metabolism , Structure-Activity Relationship , Tumor Suppressor Protein p53/metabolism
6.
ACS Med Chem Lett ; 7(3): 324-9, 2016 Mar 10.
Article in English | MEDLINE | ID: mdl-26985323

ABSTRACT

A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23-ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described.

7.
Bioorg Med Chem Lett ; 26(7): 1803-8, 2016 Apr 01.
Article in English | MEDLINE | ID: mdl-26927423

ABSTRACT

The mammalian Janus Kinases (JAK1, JAK2, JAK3 and TYK2) are intracellular, non-receptor tyrosine kinases whose activities have been associated in the literature and the clinic with a variety of hyperproliferative diseases and immunological disorders. At the onset of the program, it was hypothesized that a JAK1 selective compound over JAK2 could lead to an improved therapeutic index relative to marketed non-selective JAK inhibitors by avoiding the clinical AEs, such as anemia, presumably associated with JAK2 inhibition. During the course of the JAK1 program, a number of diverse chemical scaffolds were identified from both uHTS campaigns and de novo scaffold design. As part of this effort, a (benz)imidazole scaffold evolved via a scaffold-hopping exercise from a mature chemical series. Concurrent crystallography-driven exploration of the ribose pocket and the solvent front led to analogs with optimized kinome and JAK1 selectivities over the JAK2 isoform by targeting several residues unique to JAK1, such as Arg-879 and Glu-966.


Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Janus Kinase 1/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyridones/chemistry , Pyridones/pharmacology , Benzimidazoles/chemical synthesis , Crystallography, X-Ray , Drug Design , Humans , Janus Kinase 1/metabolism , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Pyridones/chemical synthesis , Structure-Activity Relationship
8.
ACS Med Chem Lett ; 6(6): 683-8, 2015 Jun 11.
Article in English | MEDLINE | ID: mdl-26101574

ABSTRACT

Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing.

9.
ACS Med Chem Lett ; 5(5): 572-5, 2014 May 08.
Article in English | MEDLINE | ID: mdl-24900882

ABSTRACT

Introduction of an aliphatic side chain to a key position of a novel piperidine-based HDM2 inhibitor scaffold resulted in significant potency gains, enabling further series progression.

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