2. Academic Validation
  3. Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors

Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors

  • ACS Med Chem Lett. 2020 Jul 15;11(8):1548-1554. doi: 10.1021/acsmedchemlett.0c00195.
Qinglin Pu 1,  Hongjun Zhang 1,  Liangqin Guo 1,  Mangeng Cheng 1,  Amy C Doty 1,  Heidi Ferguson 1,  Xavier Fradera 1,  Charles A Lesburg 1,  Meredeth A McGowan 1,  J Richard Miller 1,  Prasanthi Geda 1,  Xuelei Song 1,  Karin Otte 1,  Nunzio Sciammetta 1,  Nicolas Solban 1,  Wensheng Yu 2,  David L Sloman 1,  Hua Zhou 1,  Alfred Lammens 3,  Lars Neumann 3,  David Jonathan Bennett 1,  Alexander Pasternak 1,  Yongxin Han 1
Affiliations

Affiliations

  • 1 Boston Discovery Chemistry, Therapeutic Modalities, Quantitative Biosciences, Discovery Pharm Science Boston/Westpoint, Computational & Structural Chemistry, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • 2 External Discovery Chemistry, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
  • 3 Proteros Biostructures GmbH, Bunsenstr. 7a, D-82152 Planegg, Martinsried, Germany.
PMID: 32832022 DOI: 10.1021/acsmedchemlett.0c00195
Abstract

Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]pentane motif. Compound 1, evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in 1 with a bicyclo[1.1.1]pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound 2 with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.

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