Thomas H Graham

Publications (6)22.32 Total impact

• Article: A new class of prolylcarboxypeptidase inhibitors, part 1: discovery and evaluation.

  Thomas H Graham, Wensheng Liu, Andreas Verras, Iyassu K Sebhat, Yusheng Xiong, Kelly Bleasby, Urmi R Bhatt, Qing Chen, Margarita Garcia-Calvo, Wayne M Geissler, [......], Zhu Shen, Xinchun Tong, Elaine C Tung, Judyann Wiltsie, Jianying Xiao, Dan Xie, Suoyu Xu, Jeffrey J Hale, Shirly Pinto, Dong-Ming Shen
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  ABSTRACT: A new structural class of potent prolylcarboxypeptidase (PrCP) inhibitors was discovered by high-throughput screening. The series possesses a tractable SAR profile with sub-nanomolar in vitro IC(50) values. Compared to prior inhibitors, the new series demonstrated minimal activity shifts in pure plasma and complete ex vivo plasma target engagement in mouse plasma at the 20 h post-dose time point (po). In addition, the in vivo level of CNS and non-CNS drug exposure was measured.
  Bioorganic & medicinal chemistry letters 03/2012; 22(8):2811-7. · 2.65 Impact Factor
• Article: A new class of prolylcarboxypeptidase inhibitors, part 2: the aminocyclopentanes.

  Thomas H Graham, Wensheng Liu, Andreas Verras, Mikhail Reibarkh, Kelly Bleasby, Urmi R Bhatt, Qing Chen, Margarita Garcia-Calvo, Wayne M Geissler, Judith N Gorski, [......], Zhu Shen, Xinchun Tong, Elaine C Tung, Judyann Wiltsie, Dan Xie, Suoyu Xu, Jianying Xiao, Jeffrey J Hale, Shirly Pinto, Dong-Ming Shen
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  ABSTRACT: A series of potent inhibitors of prolylcarboxypeptidase (PrCP) was developed by modifying a lead structure that was discovered by high-throughput screening. The tert-butyl pyrrolidine was replaced by an aminocyclopentane to reduce the metabolic liabilities of the original lead. The compounds demonstrated sub-nanomolar in vitro IC(50) values, minimal activity shifts in pure plasma and improved pharmacokinetics. Complete ex vivo plasma target engagement was achieved with low brain exposure at the 20 h time point following p.o. dosing in a mouse. The results indicate that the aminocyclopentanes are useful tools for studying the therapeutic potential of peripheral (non-CNS) PrCP inhibition.
  Bioorganic & medicinal chemistry letters 03/2012; 22(8):2818-22. · 2.65 Impact Factor
• Article: Discovery of aminoheterocycles as potent and brain penetrant prolylcarboxypeptidase inhibitors.

  Zhicai Wu, Cangming Yang, Thomas H Graham, Andreas Verras, Renee M Chabin, Suoyu Xu, Xinchun Tong, Dan Xie, Mike E Lassman, Urmi R Bhatt, Margarita M Garcia-Calvo, Zhu Shen, Qing Chen, Kelly Bleasby, Ranabir Sinharoy, Jeffrey J Hale, James R Tata, Shirly Pinto, Steven L Colletti, Dong-Ming Shen
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  ABSTRACT: Efforts were dedicated to develop potent and brain penetrant prolylcarboxypeptidase (PrCP) inhibitors by replacing the amide group of original leads 1 and 2 with heterocycles. Aminopyrimidines including compound 32a were identified to display good PrCP inhibitory activity (32a, IC(50)=43 nM) and impressive ability to penetrate brain in mice (brain/plasma ratio: 1.4).
  Bioorganic & medicinal chemistry letters 02/2012; 22(4):1727-30. · 2.65 Impact Factor
• Article: A method for the reductive scission of heterocyclic thioethers.

  Thomas H Graham, Wensheng Liu, Dong-Ming Shen
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  ABSTRACT: A mild, chemoselective, and generally high-yielding method for the reductive scission of heterocyclic thioethers is described. Suitable heterocycles have a thioether substituent at the 2-position relative to a ring heteroatom. The convenient and straightforward method is demonstrated with reactants which are not compatible with the standard Raney nickel conditions such as sulfides, sulfones, and thiophenes. In addition, benzyl esters, benzyl amides, and benzyl carbamates are tolerated by the reductive reaction conditions.
  Organic Letters 11/2011; 13(23):6232-5. · 5.86 Impact Factor
• Article: The discovery of non-benzimidazole and brain-penetrant prolylcarboxypeptidase inhibitors.

  Thomas H Graham, Hong C Shen, Wensheng Liu, Yusheng Xiong, Andreas Verras, Kelly Bleasby, Urmi R Bhatt, Renee M Chabin, Dunlu Chen, Qing Chen, [......], Zhu Shen, Xinchun Tong, Elaine C Tung, Dan Xie, Suoyu Xu, Steven L Colletti, James R Tata, Jeffrey J Hale, Shirly Pinto, Dong-Ming Shen
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  ABSTRACT: Novel prolylcarboxypeptidase (PrCP) inhibitors with nanomolar IC(50) values were prepared by replacing the previously described dichlorobenzimidazole-substituted pyrrolidine amides with a variety of substituted benzylamine amides. In contrast to prior series, the compounds demonstrated minimal inhibition shift in whole serum and minimal recognition by P-glycoprotein (P-gp) efflux transporters. The compounds were also cell permeable and demonstrated in vivo brain exposure. The in vivo effect of compound (S)-6e on weight loss in an established diet-induced obesity (eDIO) mouse model was studied.
  Bioorganic & medicinal chemistry letters 10/2011; 22(1):658-65. · 2.65 Impact Factor
• Article: A direct synthesis of oxazoles from aldehydes.

  Thomas H Graham
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  ABSTRACT: An expedient method for the direct conversion of aldehydes to 2,4-disubstituted oxazoles is presented. The method relies on the oxidation of an oxazolidine formed from the condensation of serine with an aldehyde and proceeds through a 2,5-dihydrooxazole intermediate. In contrast to standard methods that start from carboxylic acids, the use of aldehydes as starting materials does not require intermediate purification and affords the oxazoles under relatively mild conditions.
  Organic Letters 08/2010; 12(16):3614-7. · 5.86 Impact Factor