2. Academic Validation
  3. The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties

The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties

  • J Med Chem. 2017 Dec 14;60(23):9676-9690. doi: 10.1021/acs.jmedchem.7b01135.
Tony Siu 1 2,  Jason Brubaker 1 2,  Peter Fuller 1 2,  Luis Torres 1 2,  Hongbo Zeng 1 2,  Joshua Close 1 2,  Dawn M Mampreian 1 2,  Feng Shi 1 2,  Duan Liu 1 2,  Xavier Fradera 1 2,  Kevin Johnson 1 2,  Nathan Bays 1 2,  Elma Kadic 1 2,  Fang He 1 2,  Peter Goldenblatt 1 2,  Lynsey Shaffer 1 2,  Sangita B Patel 1 2,  Charles A Lesburg 1 2,  Carla Alpert 1 2,  Lauren Dorosh 1 2,  Sujal V Deshmukh 1 2,  Hongshi Yu 1 2,  Joel Klappenbach 1 2,  Fiona Elwood 1 2,  Christopher J Dinsmore 1 2,  Rafael Fernandez 1 2,  Lily Moy 1 2,  Jonathan R Young 1 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, ‡Department of Discovery Process Chemistry, §Department of Modeling & Informatics, ∥Department of In Vitro Pharmacology, ⊥Department of Structural Chemistry, #Department of Pharmacokinetics Pharmacodynamics and Drug Metabolism, ∇Department of Discovery Pharmaceutical Sciences, ○Department of Molecular Biomarkers, ¶Department of In Vivo Pharmacology, $Department of Respiratory and Immunology, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • 2 Department of Chemistry and ◇Department of Biology, Pharmaron Beijing Co. Ltd , 6 Taihe Road BDA, Beijing 100176, P.R. China.
PMID: 29156136 DOI: 10.1021/acs.jmedchem.7b01135
Abstract

The discovery of a potent selective low dose Janus kinase 1 (JAK1) inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the discovery of compound 28.

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