Timothy D. Gross
Neurocrine Biosciences
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Timothy D. Gross.
Bioorganic & Medicinal Chemistry Letters | 2002
Yun-Fei Zhu; R. Scott Struthers; Patrick J. Connors; Yinghong Gao; Timothy D. Gross; John Saunders; Keith M. Wilcoxen; Greg J. Reinhart; Nicholas Ling; Chen Chen
Initial SAR studies on 1-aminomethyl-2-aryl-3-cyano-pyrrolo[1,2-a]pyrimid-7-one-6-carboxylates as human GnRH receptor antagonists were discussed. 2-(2-Methylaminoethyl)pyridine was discovered to be a key feature for generating active compounds. The best compound from the series had 25 nM (K(i)) binding affinity to human GnRH receptor.
Bioorganic & Medicinal Chemistry Letters | 2002
Fabio C. Tucci; Yun-Fei Zhu; Zhiqiang Guo; Timothy D. Gross; Patrick J. Connors; R. Scott Struthers; Greg J. Reinhart; Xiao-Chuan Wang; John Saunders; Chen Chen
A new class of small molecule GnRH antagonists, the 7-aryl-8-fluoro-pyrrolo[1,2-a]pyrimid-4-ones, was designed and a novel synthesis for these compounds was developed. The synthesis utilizes a base-catalyzed intramolecular cyclization of fluoromethyl pyrimidone 5 to generate the bicyclic core. Amongst the compounds synthesized, we discovered some highly potent GnRH receptor antagonists (e.g., 12, K(i)=9 nM), which showed enhanced stability towards acidic physiological conditions compared to the des-fluoro analogues.
Bioorganic & Medicinal Chemistry Letters | 2003
Fabio C. Tucci; Yun-Fei Zhu; Zhiqiang Guo; Timothy D. Gross; Patrick J. Connors; R. Scott Struthers; Greg J. Reinhart; John Saunders; Chen Chen
A new class of small molecule GnRH antagonists, the 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils, was designed and a novel stereoselective synthesis for these compounds was developed. The stereochemical integrities of key intermediates (S)-6 and (R)-6 were confirmed by a combination of X-ray crystallography and chiral HPLC determinations. SAR studies were performed, which allowed the identification of derivatives (R)-9f, (R)-9h and (R)-12 as potent hGnRH antagonists (K(i)=20 nM).
Bioorganic & Medicinal Chemistry Letters | 2002
Keith M. Wilcoxen; Yun-Fei Zhu; Patrick J. Connors; John Saunders; Timothy D. Gross; Yinghong Gao; Greg J. Reinhart; R. Scott Struthers; Chen Chen
SAR studies of 2-arylimidazolo[1,2-a]pyrimid-5-ones 10a-m, which were derived from initial lead 3a, resulted in the discovery of a series of potent nonpeptide human GnRH receptor antagonists. Compounds with good potency (e.g., 10e, K(i)=7.5 nM) were prepared by introduction of a 2-(2-pyridyl)ethyl at the basic nitrogen and a 3-pentyl ester at the 6-position of the bicyclic core.
Bioorganic & Medicinal Chemistry Letters | 2002
Yun-Fei Zhu; Keith M. Wilcoxen; John Saunders; Zhiqiang Guo; Yinghong Gao; Patrick J. Connors; Timothy D. Gross; Fabio C. Tucci; R. Scott Struthers; Greg J. Reinhart; Qiu Xie; Chen Chen
In the process of developing GnRH receptor antagonists, a novel base-catalyzed cyclization of compounds 5a-b was discovered, which led to the formation of the 2-aryl pyrrolo[1,2-a]pyrimid-7-one core structures 6a-b. These intermediates were further modified at positions 1, 2, 4 and 6 to afford a series of potent GnRH antagonists with low nanomolar K(i) values.
Bioorganic & Medicinal Chemistry Letters | 2002
Timothy D. Gross; Yun-Fei Zhu; John Saunders; Keith M. Wilcoxen; Yinghong Gao; Patrick J. Connors; Zhiqiang Guo; R. Scott Struthers; Greg J. Reinhart; Chen Chen
SAR studies of lead GnRH receptor antagonists 2a and 2b reported earlier resulted in the discovery of compound 10b which showed much higher potency (K(i)=4.6 nM, compared with 2b, K(i)=230 nM) in which the 7-position of the imidazolo[1,2-a]pyrimidone core was substituted with a methyl group, and the ester at the 6-position was replaced by the 3-methoxyphenyl group.
Bioorganic & Medicinal Chemistry Letters | 2003
Zhiqiang Guo; Yun-Fei Zhu; Fabio C. Tucci; Yinghong Gao; R. Scott Struthers; John Saunders; Timothy D. Gross; Qiu Xie; Greg J. Reinhart; Chen Chen
The novel synthesis and SAR studies of 6-methyluracils as human GnRH receptor antagonists are discussed. Introduction of a small methyl substituent at the beta-position from N3 of the uracil improved the GnRH binding potency by 5- to 10-fold. The best compound from the series had binding affinity of 5 nM (K(i)) to the human GnRH receptor.
Bioorganic & Medicinal Chemistry Letters | 2003
Yun-Fei Zhu; Xiao-Chuan Wang; Patrick J. Connors; Keith M. Wilcoxen; Yinghong Gao; Raymond S. Gross; Nathalie Strack; Timothy D. Gross; James R. McCarthy; Qiu Xie; Nicholas Ling; Chen Chen
4-benzylquinolines 5, based on a series of isoquinolines 1, were prepared and tested as inhibitors of the IGF/IGFBP-3 complex based on their ability to displace IGF-I from its binding to IGF-binding protein-3. SAR studies on the 6,7-dihydroxy moiety of the quinoline 5a showed that the catecol moiety could be replaced with other functional groups. Computational modeling of the 5a/mini-IGFBP-5 complex revealed the possible binding site of 5a on IGFBP-5.
Bioorganic & Medicinal Chemistry Letters | 2003
Yun-Fei Zhu; Keith M. Wilcoxen; Timothy D. Gross; Patrick J. Connors; Nathalie Strack; Raymond S. Gross; Charles Q. Huang; James R. McCarthy; Qiu Xie; Nicholas Ling; Chen Chen
A series of 1-benzoyl isoquinolines, based on compound 1, was synthesized and evaluated for their ability to displace IGF-I from its complex with IGF-binding protein-3. Successful modifications of 1 included the replacement of the 3,4-dihydroxybenzoyl group with a substituted benzyl group. These alternations culminated in the discovery of compounds such as 7o which had excellent in vitro potency (K(i)=9.4 nM) but with one less of the labile catechol functionality of 1.
Bioorganic & Medicinal Chemistry Letters | 2008
Liren Zhao; Zhiqiang Guo; Yongsheng Chen; Tao Hu; Dongpei Wu; Yun-Fei Zhu; Martin W. Rowbottom; Timothy D. Gross; Fabio C. Tucci; R. Scott Struthers; Qiu Xie; Chen Chen
Optimization of a series of uracils bearing a 2-fluoro- or 2-chloro-3-methoxyphenyl group at the 5-position resulted in compounds such as 3d and 3f with subnanomolar binding affinity at the human GnRH receptor. While the 2-fluoro-3-methoxyphenyl compound 3a was characterized as a mixture of interchangeable atropisomers, the diastereoisomers of 2-chloro-3-methoxyphenyl analogs were separated. It was found that the aR-atropisomer was much more potent than the aS-isomer based on the X-ray crystal structure of 3h-II.