2. Academic Validation
  3. Selective IKur Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide

Selective IKur Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide

  • J Med Chem. 2017 May 11;60(9):3795-3803. doi: 10.1021/acs.jmedchem.6b01889.
Prashantha Gunaga 1 2,  John Lloyd 1 2,  Somanadham Mummadi 1 2,  Abhisek Banerjee 1 2,  Naveen Kumar Dhondi 1 2,  James Hennan 1 2,  Veena Subray 1 2,  Ramya Jayaram 1 2,  Nagendra Rajugowda 1 2,  Kommuri Umamaheshwar Reddy 1 2,  Duraimurugan Kumaraguru 1 2,  Umasankar Mandal 1 2,  Dasthagiri Beldona 1 2,  Ashok Kumar Adisechen 1 2,  Navnath Yadav 1 2,  Jayakumar Warrier 1 2,  James A Johnson 1 2,  Harinath Sale 1 2,  Siva Prasad Putlur 1 2,  Ajay Saxena 1 2,  Anjaneya Chimalakonda 1 2,  Sandhya Mandlekar 1 2,  MaryLee Conder 1 2,  Dezhi Xing 1 2,  Arun Kumar Gupta 1 2,  Anuradha Gupta 1 2,  Richard Rampulla 1 2,  Arvind Mathur 1 2,  Paul Levesque 1 2,  Ruth R Wexler 1 2,  Heather J Finlay 1 2
Affiliations

Affiliations

  • 1 Department of Discovery Chemistry, ‡Department of Biology, and §Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Research and Development , P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • 2 Department of Discovery Chemistry, Department of Biology, @Department of Biopharmaceutics, #Department of Pharmaceutical Candidate Optimization, and ∇Biocon BMS R&D Center, Syngene International Limited, BMS India Pvt. Limited , Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560099, India.
PMID: 28418664 DOI: 10.1021/acs.jmedchem.6b01889
Abstract

We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and CA channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.

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