Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists |
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| Institution: | 1. Department of Medicinal Chemistry, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom;2. Department of Respiratory Biology, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom;3. WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom;4. UK Analytical Chemistry, Platform Technology & Science, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom;1. Natural Products Chemistry Division, CSIR-North-East Institute of Science & Technology, Jorhat 785006, Assam, India;2. Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India;1. Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK;2. Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA;1. Institute for Pharmacogenetics, Medical Research Centre, University Duisburg-Essen, Germany;2. Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard-Karls-University Tübingen, Germany;3. Occupational Medicine, Friedrich Alexander-University Erlangen, Germany;4. Research Center Borstel, Leibniz Center for Medicine and Biosciences Borstel, Germany;5. Institute for Parasitology, University of Veterinary Medicine Hannover, Germany;1. INQUISUR-CONICET, Departamento de Química, Universidad Nacional del Sur, Av. Alem 1253, B8000CPB Bahía Blanca, Argentina;2. UMYMFOR (CONICET-UBA) and Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, 1428 Buenos Aires, Argentina;3. INIBIBB-CONICET, Instituto de Investigaciones Bioquímicas de Bahía Blanca, Camino La Carrindanga km. 7, B8000FWB Bahía Blanca, Argentina;4. Gerencia de Investigación y Aplicaciones, Centro Atómico Constituyentes, Comisión Nacional de Energía Atómica, Av. Gral. Paz 1499, 1650 San Martin, Buenos Aires, Argentina;5. Escuela de Ciencia y Tecnología, Universidad Nacional General San Martín, Martín de Irigoyen 3100, 1650 San Martín, Buenos Aires, Argentina |
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| Abstract: | A knowledge-based library of 2,3-dichlorophenylsulfonyl derivatives of commercially available aryl amines was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. Hits were required to be more potent than an existing indazole series, have better physicochemical properties (c log P <3.5, chrom log D7.4 <5.3 and CLND solubility >116 μg/mL), and be stable to acid and light. The benzimidazol-2-one core was identified as a hit suitable for further investigation. Substitution at N1 with small alkyl groups was tolerated; however, these analogues were inactive in the whole blood assay (pA2 <5). Azabenzimidazolone analogues were all found to be active, with compound 38 exhibiting whole blood activity of 6.1, low molecular weight (389) and chrom log D7.4 (2.4), high LE (0.43), and solubility (152 μg/mL). In addition, 38 had human serum albumin binding of around 93% and met all the criteria for progression to lead optimisation. |
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| Keywords: | CCR4 antagonist Benzimidazolone Azabenzimidazolone |
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