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Andrew W Stamford,
Jack D Scott,
Sarah W Li,
Suresh Babu,
Dawit Tadesse,
Rachael Hunter,
Yusheng Wu,
Jeffrey Misiaszek,
Jared N Cumming,
Eric J Gilbert, [......],
Johannes H Voigt,
Matthew E Kennedy,
Xia Chen,
Reshma Kuvelkar,
Robert Hodgson,
Lynn A Hyde,
Kathleen Cox,
Leonard Favreau,
Eric M Parker,
William J Greenlee
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ABSTRACT: Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aβ levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aβ40 levels when administered orally to rats.
ACS Medicinal Chemistry Letters 11/2012; 3(11):897-902. · 3.36 Impact Factor
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Mihirbaran Mandal,
Zhaoning Zhu,
Jared N Cumming,
Xiaoxiang Liu,
Corey Strickland,
Robert D Mazzola,
John P Caldwell,
Prescott Leach,
Michael Grzelak,
Lynn Hyde, [......],
Kathleen Cox,
Peter Orth,
Alexei Buevich,
Johannes Voigt,
Hongwu Wang,
Irina Kazakevich, Brian A McKittrick,
William Greenlee,
Eric M Parker,
Andrew W Stamford
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ABSTRACT: On the basis of our observation that the biaryl substituent of iminopyrimidinone 7 must be in a pseudoaxial conformation to occupy the contiguous S1-S3 subsites of BACE1, we have designed a novel fused bicyclic iminopyrimidinone scaffold intended to favor this bioactive conformation. Strategic incorporation of a nitrogen atom in the new constrained ring allowed us to develop SAR around the S2' binding pocket and ultimately resulted in analogues with low nanomolar potency for BACE1. In particular, optimization of the prime side substituent led to major improvements in potency by displacement of two conserved water molecules from a region near S2'. Further optimization of the pharmacokinetic properties of this fused pyrrolidine series, in conjunction with facile access to a rat pharmacodynamic model, led to identification of compound 43, which is an orally active, brain penetrant inhibitor that reduces Aβ(40) in the plasma, CSF, and cortex of rats in a dose-dependent manner.
Journal of Medicinal Chemistry 09/2012; · 4.80 Impact Factor
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Jared N Cumming,
Elizabeth M Smith,
Lingyan Wang,
Jeffrey Misiaszek,
James Durkin,
Jianping Pan,
Ulrich Iserloh,
Yusheng Wu,
Zhaoning Zhu,
Corey Strickland, [......],
Matthew E Kennedy,
Reshma Kuvelkar,
Lynn A Hyde,
Kathleen Cox,
Leonard Favreau,
Michael F Czarniecki,
William J Greenlee, Brian A McKittrick,
Eric M Parker,
Andrew W Stamford
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ABSTRACT: From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aβ following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.
Bioorganic & medicinal chemistry letters 02/2012; 22(7):2444-9. · 2.65 Impact Factor
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Xianhai Huang,
Jing Su,
Ashwin U Rao,
Haiqun Tang,
Wei Zhou,
Xiaohong Zhu,
Xiao Chen,
Zhidan Liu,
Ying Huang,
Sylvia Degrado,
Dong Xiao,
Jun Qin,
Robert Aslanian, Brian A McKittrick,
Scott Greenfeder,
Margaret van Heek,
Madhu Chintala,
Anandan Palani
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ABSTRACT: Based on in house screening lead compound 1 for the NAR project, SAR studies have been focused on the modification of the C2 ethers of the pyrimidinedione core structure. In this effort, an unpredictable SAR trend was overcome in the alkyl ether and arylalkyl ether series to identify compound 24 with improved in vitro activity compared to nicotinic acid. More consistent and predictable SAR was achieved in the propargyl ether series. Lead compound 41 was identified with good in vitro and in vivo activity in rat, and much improved rat PK profile.
Bioorganic & medicinal chemistry letters 12/2011; 22(2):854-8. · 2.65 Impact Factor
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ABSTRACT: SAR exploration at C-6 and C-8 positions of the tricyclic sulfone series was carried out. Several functional groups were found to be well tolerated at C-6 and C-8 positions. Selective combination of C-6 and C-8 modification resulted in new tricyclic sulfone analogs with efficacy in in vivo mouse Aβ(40) lowering model.
Bioorganic & medicinal chemistry letters 06/2011; 21(11):3447-51. · 2.65 Impact Factor
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Elizabeth M Smith,
Steve Sorota,
Hyunjin M Kim, Brian A McKittrick,
Terry L Nechuta,
Chad Bennett,
Chad Knutson,
Duane A Burnett,
Jane Kieselgof,
Zheng Tan, [......],
Xiaoping Zhou,
Yu-Ping Jia,
Zoe Dong,
Debbie Mullins,
Xiaoping Zhang,
Tony Priestley,
Craig C Correll,
Deen Tulshian,
Michael Czarniecki,
William J Greenlee
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ABSTRACT: A series of spiro-azetidines and azetidinones has been evaluated as novel blockers of the T-type calcium channel (Ca(V)3.2) which is a new therapeutic target for the potential treatment of both inflammatory and neuropathic pain. Confirmation and optimization of the potency, selectivity and DMPK properties of leads will be described.
Bioorganic & medicinal chemistry letters 08/2010; 20(15):4602-6. · 2.65 Impact Factor
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Yu-Sen Wang,
Corey Strickland,
Johannes H Voigt,
Matthew E Kennedy,
Brian M Beyer,
Mary M Senior,
Elizabeth M Smith,
Terry L Nechuta,
Vincent S Madison,
Michael Czarniecki, Brian A McKittrick,
Andrew W Stamford,
Eric M Parker,
John C Hunter,
William J Greenlee,
Daniel F Wyss
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ABSTRACT: Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification of an isothiourea hit with a K(d) of 15 microM for BACE-1. NMR data and the crystal structure revealed that this hit makes H-bond interactions with the two catalytic aspartates, occupies the nonprime side region of the active site of BACE-1, and extends toward the S3 subpocket (S3sp). A focused NMR-based search for heterocyclic isothiourea isosteres resulted in several distinct classes of BACE-1 active site directed compounds with improved chemical stability and physicochemical properties. The strategy for optimization of the 2-aminopyridine lead series to potent inhibitors of BACE-1 was demonstrated. The structure-based design of a cyclic acylguanidine lead series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper
Journal of Medicinal Chemistry 02/2010; 53(3):942-50. · 4.80 Impact Factor
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Zhaoning Zhu,
Zhong-Yue Sun,
Yuanzan Ye,
Johannes Voigt,
Corey Strickland,
Elizabeth M Smith,
Jared Cumming,
Lingyan Wang,
Jesse Wong,
Yu-Sen Wang, [......],
Xia Chen,
Reshma Kuvelkar,
Matthew E Kennedy,
Leonard Favreau,
Eric Parker, Brian A McKittrick,
Andrew Stamford,
Michael Czarniecki,
William Greenlee,
John C Hunter
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ABSTRACT: A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit (3), with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores (10 and 23) were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180 degrees in relation to the other. The amidine structural motif within each core forms a bidentate interaction with a different aspartic acid of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates, as revealed by 3. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.
Journal of Medicinal Chemistry 02/2010; 53(3):951-65. · 4.80 Impact Factor
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Li Qiang,
T K Sasikumar,
Duane A Burnett,
Jing Su,
Haiqun Tang,
Yuanzan Ye,
Robert D Mazzola,
Zhaoning Zhu, Brian A McKittrick,
William J Greenlee,
Ahmad Fawzi,
Michelle Smith,
Hongtao Zhang,
Jean E Lachowicz
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ABSTRACT: A series of novel dopamine D(1) antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D(1) activity and more than 1000-fold selectivity over D(2). We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D(1) antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166.
Bioorganic & medicinal chemistry letters 02/2010; 20(3):836-40. · 2.65 Impact Factor
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Yu-Sen Wang,
Corey Strickland,
Johannes H. Voigt,
Matthew E. Kennedy,
Brian M. Beyer,
Mary M. Senior,
Elizabeth M. Smith,
Terry L. Nechuta,
Vincent S. Madison,
Michael Czarniecki, Brian A. McKittrick,
Andrew W. Stamford,
Eric M. Parker,
John C. Hunter,
William J. Greenlee,
Daniel F. Wyss
[show abstract]
[hide abstract]
ABSTRACT: Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification of an isothiourea hit with a Kd of 15 μM for BACE-1. NMR data and the crystal structure revealed that this hit makes H-bond interactions with the two catalytic aspartates, occupies the nonprime side region of the active site of BACE-1, and extends toward the S3 subpocket (S3sp). A focused NMR-based search for heterocyclic isothiourea isosteres resulted in several distinct classes of BACE-1 active site directed compounds with improved chemical stability and physicochemical properties. The strategy for optimization of the 2-aminopyridine lead series to potent inhibitors of BACE-1 was demonstrated. The structure-based design of a cyclic acylguanidine lead series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper ( J. Med. Chem. 2010, 53, DOI:10.1021/jm901408p).
12/2009;
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Jack D Scott,
Michael W Miller,
Sarah W Li,
Sue-Ing Lin,
Henry A Vaccaro,
Liwu Hong,
Deborra E Mullins,
Mario Guzzi,
Jay Weinstein,
Robert A Hodgson,
Geoffrey B Varty,
Andrew W Stamford,
Tin-Yau Chan, Brian A McKittrick,
William J Greenlee,
Tony Priestley,
Eric M Parker
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ABSTRACT: Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists that possessed moderate to high selectivity over other receptors.
Bioorganic & medicinal chemistry letters 09/2009; 19(21):6018-22. · 2.65 Impact Factor
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ABSTRACT: A series of spiro-piperidine azetidinone were synthesized and evaluated as potential TRPV1 antagonists. An important issue of plasma stability was investigated and resolved. Further focused SAR study lead to the discovery of a potent antagonist with good oral pharmacokinetic profile in rat.
Bioorganic & medicinal chemistry letters 01/2009; 19(3):783-7. · 2.65 Impact Factor
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Jing Su,
Haiqun Tang, Brian A McKittrick,
Huizhong Gu,
Tao Guo,
Gang Qian,
Duane A Burnett,
John W Clader,
William J Greenlee,
Brian E Hawes,
Kim O'neill,
Brian Spar,
Blair Weig,
Timothy Kowalski,
Steve Sorota
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ABSTRACT: To address the hERG liability of MCHR1 antagonists such as 1 and 2, new analogs such as 4 and 5 that incorporated a polar heteroaryl group were designed and synthesized. Biological evaluation confirmed that these new analogs retained MCH R1 activity with greatly attenuated hERG liabilities as indicated in the Rb efflux assay.
Bioorganic & Medicinal Chemistry Letters 10/2007; 17(17):4845-50. · 2.55 Impact Factor
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Jing Su, Brian A McKittrick,
Haiqun Tang,
Duane A Burnett,
John W Clader,
William J Greenlee,
Brian E Hawes,
Kim O'Neill,
Brian Spar,
Blair Weig,
Timothy Kowalski,
Steve Sorota,
Cheng Li,
Tongtong Liu
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ABSTRACT: To improve the ex vivo potency of MCH inhibitor 1a and to address its hERG liability, a structure-activity study was carried out, focusing on three regions of the lead structure. Introduction of new side chains with basic nitrogen improved in vitro and ex vivo bindings. Many potent compounds with K(i)<10nM were discovered (compounds 6a-j) and several compounds (14-17) had excellent ex vivo binding at 6h and 24h. Attenuating the basicity of nitrogen on the side chain, and in particular, introduction of a polar group such as aminomethyl on the distal phenyl ring significantly lowered the hERG activity. Further replacement of the distal phenyl group with heteroaryl groups in the cyclohexene series provided compounds such as 28l with excellent ex vivo activity with much reduced hERG liability.
Bioorganic & Medicinal Chemistry 09/2007; 15(16):5369-85. · 2.92 Impact Factor
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Dmitri A Pissarnitski,
Theodros Asberom,
Thomas A Bara,
Alex V Buevich,
John W Clader,
William J Greenlee,
Henry S Guzik,
Hubert B Josien,
Wei Li,
Michael McEwan, [......],
Terry L Nechuta,
Eric M Parker,
Lisa Sinning,
Elizabeth M Smith,
Lixin Song,
Henry A Vaccaro,
Johannes H Voigt,
Lili Zhang,
Qi Zhang,
Zhiqiang Zhao
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ABSTRACT: A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.
Bioorganic & Medicinal Chemistry Letters 02/2007; 17(1):57-62. · 2.55 Impact Factor
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ABSTRACT: A structure-activity study based on the core structure of clozapine 1b was accomplished by utilizing high-throughput synthesis. Several focused libraries were designed and synthesized to quickly develop SAR. The results indicate that by varying different regions of clozapine, both D(1)-selective and D(2)-selective compounds can be obtained.
Bioorganic & Medicinal Chemistry Letters 10/2006; 16(17):4548-53. · 2.55 Impact Factor
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[show abstract]
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ABSTRACT: A structure-activity study on benzylpiperidine 1 was accomplished by utilizing high-throughput synthesis. Three focused libraries were designed and synthesized to quickly develop SAR. Further optimization led to the discovery of compound 2, an MCH receptor R1 antagonist with over 400-fold improvement in biological activity over the original lead.
Bioorganic & Medicinal Chemistry 04/2005; 13(5):1829-36. · 2.92 Impact Factor
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[show abstract]
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ABSTRACT: We have discovered highly potent, selective sulfide M(2) receptor antagonists with low molecular weight and different structural features compared with our phase I clinical candidate Sch 211803. Analogue 30 showed superior M(2) receptor selectivity profile over Sch 211803. More importantly, this study provided new leads for the discovery of M(2) receptor antagonists as potential drug candidates.
Bioorganic & Medicinal Chemistry Letters 05/2002; 12(7):1087-91. · 2.55 Impact Factor
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Jing Su,
Haiqun Tang, Brian A. McKittrick,
Huizhong Gu,
Tao Guo,
Gang Qian,
Duane A. Burnett,
John W. Clader,
William J. Greenlee,
Brian E. Hawes,
Kim O’Neill,
Brian Spar,
Blair Weig,
Timothy Kowalski,
Steve Sorota
Bioorganic & Medicinal Chemistry Letters. 17(17):4845-4850.
