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Anthony D William,
Angeline C-H Lee,
Kee Chuan Goh,
Stéphanie Blanchard,
Anders Poulsen,
Ee Ling Teo,
Harish Nagaraj,
Chai Ping Lee,
Haishan Wang,
Meredith Williams,
Eric T Sun, Changyong Hu,
Ramesh Jayaraman,
Mohammed Khalid Pasha,
Kantharaj Ethirajulu,
Jeanette M Wood,
Brian W Dymock
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ABSTRACT: Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
Journal of Medicinal Chemistry 12/2011; 55(1):169-96. · 4.80 Impact Factor
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Ramesh Jayaraman,
Venkatesh Pilla Reddy,
Mohammed Khalid Pasha,
Haishan Wang,
Kanda Sangthongpitag,
Pauline Yeo, Chang Yong Hu,
Xiaofeng Wu,
Liu Xin,
Evelyn Goh,
Lee Sun New,
Kantharaj Ethirajulu
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ABSTRACT: The preclinical absorption, distribution, metabolism, and excretion (ADME) properties of Pracinostat [(2E)-3-[2-butyl-1-[2-(diethylamino) ethyl]-1H-benzimidazol-5-yl]-N-hydroxyarylamide hydrochloride; SB939], an orally active histone deacetylase inhibitor, were characterized and its human pharmacokinetics (PK) was predicted using Simcyp and allometric scaling. SB939 showed high aqueous solubility with high Caco-2 permeability. Metabolic stability was relatively higher in dog and human liver microsomes than in mouse and rat. The major metabolites formed in human liver microsomes were also observed in preclinical species. Human cytochrome P450 (P450) phenotyping showed that SB939 was primarily metabolized by CYP3A4 and CYP1A2. SB939 did not significantly inhibit human CYP3A4, 1A2, 2D6, and 2C9 (>25 μM) but inhibited 2C19 (IC(50) = 5.8 μM). No significant induction of human CYP3A4 and 1A2 was observed in hepatocytes. Plasma protein binding in mouse, rat, dog, and human ranged between ∼84 and 94%. The blood-to-plasma ratio was ∼1.0 in human blood. SB939 showed high systemic clearance (relative to liver blood flow) of 9.2, 4.5, and 1.5 l · h(-1) · kg(-1) and high volume of distribution at steady state (>0.6 l/kg) of 3.5, 1.7, and 4.2 l/kg in mouse, rat, and dog, respectively. The oral bioavailability was 34, 65, and ∼3% in mice, dogs, and rats, respectively. The predicted oral PK profile and parameters of SB939, using Simcyp and allometric scaling, were in good agreement with observed data in humans. Simcyp predictions showed lack of CYP3A4 and 2C19 drug-drug interaction potential for SB939. In summary, the preclinical ADME of SB939 supported its preclinical and clinical development as an oral drug candidate.
Drug metabolism and disposition: the biological fate of chemicals 08/2011; 39(12):2219-32. · 3.74 Impact Factor
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Haishan Wang,
Niefang Yu,
Dizhong Chen,
Ken Chi Lik Lee,
Pek Ling Lye,
Joyce Wei Wei Chang,
Weiping Deng,
Melvin Chi Yeh Ng,
Ting Lu,
Mui Ling Khoo, [......],
Kay Lin Goh,
Hwee Hoon Khng,
Siok Kun Goh,
Pauline Yeo,
Xin Liu,
Zahid Bonday,
Jeanette M Wood,
Brian W Dymock,
Ethirajulu Kantharaj,
Eric T Sun
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ABSTRACT: A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC(50)), liver microsomal stability (t(1/2)), cytochrome P450 inhibitory (3A4 IC(50)), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.
Journal of Medicinal Chemistry 06/2011; 54(13):4694-720. · 4.80 Impact Factor
