Selective I Kur 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

• Published in: Journal of medicinal chemistry Vol. 60; no. 9; pp. 3795 - 3803
• Main Authors: Gunaga, Prashantha, Lloyd, John, Mummadi, Somanadham, Banerjee, Abhisek, Dhondi, Naveen Kumar, Hennan, James, Subray, Veena, Jayaram, Ramya, Rajugowda, Nagendra, Umamaheshwar Reddy, Kommuri, Kumaraguru, Duraimurugan, Mandal, Umasankar, Beldona, Dasthagiri, Adisechen, Ashok Kumar, Yadav, Navnath, Warrier, Jayakumar, Johnson, James A, Sale, Harinath, Putlur, Siva Prasad, Saxena, Ajay, Chimalakonda, Anjaneya, Mandlekar, Sandhya, Conder, MaryLee, Xing, Dezhi, Gupta, Arun Kumar, Gupta, Anuradha, Rampulla, Richard, Mathur, Arvind, Levesque, Paul, Wexler, Ruth R, Finlay, Heather J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.05.2017; Amer Chemical Soc
• Subjects: Animals; Atrial Fibrillation - drug therapy; Carbon-13 Magnetic Resonance Spectroscopy; Chemistry, Medicinal; Dogs; Life Sciences & Biomedicine; Mass Spectrometry; Pharmacology & Pharmacy; Potassium Channel Blockers - pharmacology; Potassium Channel Blockers - therapeutic use; Proton Magnetic Resonance Spectroscopy; Quinazolines - chemistry; Quinazolines - pharmacology; Quinazolines - therapeutic use; Rabbits; Science & Technology; Sodium Channel Blockers - pharmacology; Sodium Channel Blockers - therapeutic use; Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; HEART; TORSADES-DE-POINTES; RECOMMENDATIONS; DRUGS; CHANNELS; VENTRICULAR MYOCYTES; MODEL; DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b01889

We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)­quinazolin-4-amine 1 as a potent I Kur 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.