公开(公告)号：US08691833B2

公开(公告)日：2014-04-08

申请号：US13415404

申请日：2012-03-08

Applicant: Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voight ,  Corey O. Strickland ,  Elizabeth M. Smith ,  Andrew W. Stamford ,  William J. Greenlee ,  Robert D. Mazzola, Jr. ,  John P. Caldwell ,  Jared N. Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Xiaoiang Liu ,  Tao Guo ,  Thuy X.E. Le ,  Kurt W. Saionz ,  Suresh D. Babu ,  Rachael C. Hunter ,  Michelle L. Morris ,  Huizhong Gu ,  Gang Qian ,  Dawit Tadesse ,  Ying Huang ,  Guoqing Li ,  Jianping Pan ,  Jeffrey A. Misiaszek ,  Gaifa Lai ,  Jingqi Duo ,  Chuanxing Qu ,  Yuefei Shao

Inventor： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voight ,  Corey O. Strickland ,  Elizabeth M. Smith ,  Andrew W. Stamford ,  William J. Greenlee ,  Robert D. Mazzola, Jr. ,  John P. Caldwell ,  Jared N. Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Xiaoiang Liu ,  Tao Guo ,  Thuy X.E. Le ,  Kurt W. Saionz ,  Suresh D. Babu ,  Rachael C. Hunter ,  Michelle L. Morris ,  Huizhong Gu ,  Gang Qian ,  Dawit Tadesse ,  Ying Huang ,  Guoqing Li ,  Jianping Pan ,  Jeffrey A. Misiaszek ,  Gaifa Lai ,  Jingqi Duo ,  Chuanxing Qu ,  Yuefei Shao

IPC: A01N43/54 ,  A61K31/505 ,  C07D239/02

CPC classification number: C07D233/88 ,  A61K31/4168 ,  A61K31/4178 ,  C07D239/22 ,  C07D401/06 ,  C07D401/10 ,  C07D403/06 ,  C07D409/04 ,  C07D409/14 ,  C07D413/04 ,  C07D417/10 ,  C07D417/14 ,  C07D495/10

Abstract: Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein each variable in Formula 1 are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. Also disclosed are methods of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic m1 agonist or m2 antagonist.

Abstract translation: 公开了式I化合物或其立体异构体，互变异构体或其药学上可接受的盐或溶剂化物，其中式1中的每个变量如说明书中所定义; 以及包含式I化合物的药物组合物。还公开了抑制天冬氨酰蛋白酶的方法，特别是治疗心血管疾病，认知和神经退行性疾病的方法，以及抑制人类免疫缺陷病毒，plasmepins，组织蛋白酶D和 原生动物酶。 还公开了使用式I化合物与胆碱酯酶抑制剂或毒蕈碱m1激动剂或m2拮抗剂组合治疗认知或神经变性疾病的方法。

公开(公告)号：US20120231017A1

公开(公告)日：2012-09-13

申请号：US13415404

申请日：2012-03-08

Applicant: ZHAONING ZHU ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voigt ,  Corey O. Strickland ,  Elizabeth M. Smith ,  Andrew Stamford ,  William J. Greenlee ,  Robert D. Mozzola ,  John P. Caldwell ,  Jared N. Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Xiaoiang Liu ,  Tao Guo ,  Thuy X. E. Le ,  Kurt W. Sainoz ,  Suresh D. Babu ,  Rachael C. Hunter ,  Michelle L. Morris ,  Huizhong Gu ,  Gang Qian ,  Dawit Tadesse ,  Ying Huang ,  Guoqing Li ,  Jianping Pan ,  Jeffrey A. Misiaszek ,  Gaifa Lai ,  Jingqi Duo ,  Chuanxing Qu ,  Yuefei Shao

Inventor： ZHAONING ZHU ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voigt ,  Corey O. Strickland ,  Elizabeth M. Smith ,  Andrew Stamford ,  William J. Greenlee ,  Robert D. Mozzola ,  John P. Caldwell ,  Jared N. Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Xiaoiang Liu ,  Tao Guo ,  Thuy X. E. Le ,  Kurt W. Sainoz ,  Suresh D. Babu ,  Rachael C. Hunter ,  Michelle L. Morris ,  Huizhong Gu ,  Gang Qian ,  Dawit Tadesse ,  Ying Huang ,  Guoqing Li ,  Jianping Pan ,  Jeffrey A. Misiaszek ,  Gaifa Lai ,  Jingqi Duo ,  Chuanxing Qu ,  Yuefei Shao

IPC: A61K39/395 ,  C07D239/70 ,  C07F5/02 ,  C07D403/10 ,  A61K31/513 ,  A61K31/506 ,  C07D409/04 ,  C07D409/14 ,  C07D401/04 ,  C07D405/14 ,  C07D417/14 ,  C07D417/04 ,  C07D413/14 ,  C07D413/10 ,  A61K31/5377 ,  A61P29/00 ,  A61P9/00 ,  A61P25/28 ,  A61P31/10 ,  A61P33/02 ,  C07D495/04 ,  A61P25/00 ,  A61P31/04 ,  C07D239/22

CPC classification number: C07D233/88 ,  A61K31/4168 ,  A61K31/4178 ,  C07D239/22 ,  C07D401/06 ,  C07D401/10 ,  C07D403/06 ,  C07D409/04 ,  C07D409/14 ,  C07D413/04 ,  C07D417/10 ,  C07D417/14 ,  C07D495/10

Abstract: Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein each variable in Formula 1 are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. Also disclosed are methods of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic m1 agonist or m2 antagonist.

公开(公告)号：US08012953B2

公开(公告)日：2011-09-06

申请号：US12571840

申请日：2009-10-01

Applicant: Andrew W. Stamford ,  Ying Huang ,  Guoqing Li ,  Corey O. Strickland ,  Johannes H. Voigt

Inventor： Andrew W. Stamford ,  Ying Huang ,  Guoqing Li ,  Corey O. Strickland ,  Johannes H. Voigt

IPC: A61K31/33 ,  C07D513/00

CPC classification number: C07D498/04 ,  C07D413/06

Abstract: Disclosed are novel compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R3, n and X are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula I. Also disclosed are methods of treating cognitive or neurodegenerative diseases such as Alzheimer's disease. Also disclosed are methods of treating a cognitive or neurodegenerative disease comprising administering to a patient I need of such treatment a combination of at least one compound of formula I and at least one compound selected from the group consisting of β-secretase inhibitors other than those of formula I, HMG-CoA reductase inhibitors, gamma-secretase inhibitors, non-steroidal anti-inflammatory agents, N-methyl-D-aspartate receptor antagonists, cholinesterase inhibitors and anti-amyloid antibodies.

Abstract translation: 公开了下式的新化合物或其药学上可接受的盐或溶剂化物，其中R1，R2，R3，n和X如说明书中所定义。 还公开了包含式I化合物的药物组合物。还公开了治疗认知或神经变性疾病如阿尔茨海默病的方法。 还公开了治疗认知或神经退行性疾病的方法，包括向需要这种治疗的患者施用至少一种式I化合物和至少一种选自除了那些的那些之外的其他化合物 式I，HMG-CoA还原酶抑制剂，γ-分泌酶抑制剂，非甾体抗炎剂，N-甲基-D-天冬氨酸受体拮抗剂，胆碱酯酶抑制剂和抗淀粉样蛋白抗体。

公开(公告)号：US07868000B2

公开(公告)日：2011-01-11

申请号：US11451541

申请日：2006-06-12

Applicant: Zhaoning Zhu ,  Brian McKittrick ,  Andrew Stamford ,  William J. Greenlee ,  Xiaoxiang Liu ,  Mihirbaran Mandal ,  Johannes H. Voigt ,  Corey O. Strickland

Inventor： Zhaoning Zhu ,  Brian McKittrick ,  Andrew Stamford ,  William J. Greenlee ,  Xiaoxiang Liu ,  Mihirbaran Mandal ,  Johannes H. Voigt ,  Corey O. Strickland

IPC: A61K31/55 ,  A61K31/53 ,  A61K31/519 ,  A01N43/62 ,  A01N43/64 ,  A01N43/90 ,  C07D253/08 ,  C07D487/00 ,  C07D491/00 ,  C07D513/00 ,  C07D515/00

CPC classification number: C07D487/04

Abstract: Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein j, k, U, W, R, R1, R2, R3, R4, R6, R7 and R7a are as described above in the specification. Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic m1 agonist or m2 antagonist.

Abstract translation: 公开了式I化合物或其立体异构体，互变异构体或其药学上可接受的盐或溶剂合物，其中j，k，U，W，R，R1，R2，R3，R4，R6，R7和R7a如上所述 规格。 还公开了抑制天冬氨酰蛋白酶的方法，特别是治疗心血管疾病，认知和神经变性疾病的方法。 还公开了使用式I化合物与胆碱酯酶抑制剂或毒蕈碱m1激动剂或m2拮抗剂组合治疗认知或神经变性疾病的方法。

公开(公告)号：US07824897B2

公开(公告)日：2010-11-02

申请号：US12702760

申请日：2010-02-09

Applicant: Brian M. Beyer ,  Richard N. Ingram ,  Peter Orth ,  Corey O. Strickland

Inventor： Brian M. Beyer ,  Richard N. Ingram ,  Peter Orth ,  Corey O. Strickland

IPC: C12N9/64 ,  C12N5/10 ,  C12Q1/37 ,  G01N31/00

CPC classification number: C12N9/6489 ,  C07K2299/00

Abstract: The present invention discloses a modified tumor necrosis factor-alpha converting enzyme (TACE) catalytic domain, that unlike the native TACE catalytic domain, is stable at high protein concentrations. The present invention further discloses methods for generating crystals of the modified TACE protein in protein-ligand complexes with a number of inhibitors. In addition, the present invention discloses methods of using the proteins, crystals and/or three-dimensional structures obtained to identify compounds that can modulate the enzymatic activity of TACE.

公开(公告)号：US07569391B2

公开(公告)日：2009-08-04

申请号：US11634737

申请日：2006-12-06

Applicant: Brian M. Beyer ,  Bruce A. Malcolm ,  Corey O. Strickland ,  Wenyan Wang ,  Eileen Wilson

Inventor： Brian M. Beyer ,  Bruce A. Malcolm ,  Corey O. Strickland ,  Wenyan Wang ,  Eileen Wilson

IPC: G01N31/00 ,  G01N33/00

CPC classification number: C12N9/6421 ,  C07K2299/00

Abstract: The present application relates to methods for growing crystals of both the uncomplexed and complexed forms of β-secretase (BACE) polypeptide. The present application also relates to crystalline forms of uncomplexed BACE and the three-dimensional structure of BACE, as determined from the crystals. In addition, the present application relates to the use of crystalline forms of BACE to identify ligands, preferably inhibitors (antagonists), which bind to, and preferably inhibit the enzymatic activity of, BACE. Furthermore, the present application relates to nucleic acid sequences encoding human BACE polypeptide, and methods for making BACE in greater quantity than prior methods, resulting in more effective crystallization.

Abstract translation: 本申请涉及用于生长未络合和复合形式的β-分泌酶（BACE）多肽的晶体的方法。 本申请还涉及未结合的BACE的晶体形式和由晶体确定的BACE的三维结构。 此外，本申请涉及BACE的结晶形式用于鉴定与BACE结合并优选抑制BACE的酶活性的配体，优选抑制剂（拮抗剂）。 此外，本申请涉及编码人BACE多肽的核酸序列和与以前的方法相比制备BACE的方法，导致更有效的结晶。

公开(公告)号：US07529628B2

公开(公告)日：2009-05-05

申请号：US11582710

申请日：2006-10-18

Applicant: Brian M. Beyer ,  Richard N. Ingram ,  Peter Orth ,  Corey O. Strickland

Inventor： Brian M. Beyer ,  Richard N. Ingram ,  Peter Orth ,  Corey O. Strickland

IPC: G01N33/48 ,  G06G7/58

CPC classification number: C12N9/6489 ,  C07K2299/00

Abstract: The present invention discloses a modified tumor necrosis factor-alpha converting enzyme (TACE) catalytic domain, that unlike the native TACE catalytic domain, is stable at high protein concentrations. The present invention further discloses methods for generating crystals of the modified TACE protein in protein-ligand complexes with a number of inhibitors. In addition, the present invention discloses methods of using the proteins, crystals and/or three-dimensional structures obtained to identify compounds that can modulate the enzymatic activity of TACE.

Abstract translation: 本发明公开了一种修饰的肿瘤坏死因子-α转化酶（TACE）催化结构域，其与天然TACE催化结构域不同，在高蛋白浓度下是稳定的。 本发明还公开了用多种抑制剂在蛋白质 - 配体复合物中产生修饰的TACE蛋白的晶体的方法。 此外，本发明公开了使用获得的蛋白质，晶体和/或三维结构来鉴定可调节TACE的酶活性的化合物的方法。

公开(公告)号：US20100292203A1

公开(公告)日：2010-11-18

申请号：US12693874

申请日：2010-01-26

Applicant: Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voigt ,  Corey O. Strickland ,  Elizabeth M. Smith ,  Andrew Stamford ,  William J. Greenlee ,  Robert D. Mazzola ,  John P. Caldwell ,  Jared N. Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Xiaoxiang Liu ,  Dawit Tadesse ,  Ying Huang ,  Guoqing Li ,  Jianping Pan

Inventor： Zhaoning Zhu ,  Brian McKittrick ,  Zhong-Yue Sun ,  Yuanzan C. Ye ,  Johannes H. Voigt ,  Corey O. Strickland ,  Elizabeth M. Smith ,  Andrew Stamford ,  William J. Greenlee ,  Robert D. Mazzola ,  John P. Caldwell ,  Jared N. Cumming ,  Lingyan Wang ,  Yusheng Wu ,  Ulrich Iserloh ,  Xiaoxiang Liu ,  Dawit Tadesse ,  Ying Huang ,  Guoqing Li ,  Jianping Pan

IPC: A61K31/505 ,  C07D239/22 ,  A61K31/55 ,  A61K31/397

CPC classification number: C07D233/88 ,  A61K31/4168 ,  A61K31/4178 ,  C07D239/22 ,  C07D401/06 ,  C07D401/10 ,  C07D403/06 ,  C07D409/04 ,  C07D409/14 ,  C07D413/04 ,  C07D417/10 ,  C07D417/14 ,  C07D495/10

Abstract: Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein W is a bond, —C(═S)—, —S(O)—, —S(O)2—, —C(═O)—, —O—, —C(R6)(R7)—, —N(R5)— or —C(═N(R5))—; X is —O—, —N(R5)— or —C(R6)(R7)—; provided that when X is —O—, U is not —O—, —S(O)—, —S(O)2—, —C(═O)— or —C(═NR5)—; U is a bond, —S(O)—, —S(O)2—, —C(O)—, —O—, —P(O)(OR15)—, —C(═NR5)—, —(C(R6)(R7))b— or —N(R5)—; wherein b is 1 or 2; provided that when W is —S(O)—, —S(O)2—, —O—, or —N(R5)—, U is not —S(O)—, —S(O)2—, —O—, or —N(R5)—; provided that when X is —N(R5)— and W is —S(O)—, —S(O)2—, —O—, or —N(R5)—, then U is not a bond; and R1, R2, R3, R4, R5, R6, and R7 are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes.Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic m1 agonist or m2 antagonist.

公开(公告)号：US20100267150A1

公开(公告)日：2010-10-21

申请号：US12723184

申请日：2010-03-12

Applicant: THOMAS E. HESSON ,  HUNG V. LE ,  YAO MA ,  VINCENT S. MADISON ,  ANTHONY F. MANNARINO ,  PAUL REICHERT ,  GERALD W. SHIPPS, JR. ,  COREY O. STRICKLAND ,  SHAHRIAR SHANE TAREMI ,  YAOLIN WANG ,  RUMIN ZHANG ,  JOSE DUCA

Inventor： THOMAS E. HESSON ,  HUNG V. LE ,  YAO MA ,  VINCENT S. MADISON ,  ANTHONY F. MANNARINO ,  PAUL REICHERT ,  GERALD W. SHIPPS, JR. ,  COREY O. STRICKLAND ,  SHAHRIAR SHANE TAREMI ,  YAOLIN WANG ,  RUMIN ZHANG ,  JOSE DUCA

IPC: G01N33/48 ,  C07K14/435

CPC classification number: C07K14/82 ,  C07K2299/00

Abstract: The present invention relates to HDM2 polypeptides and mutants thereof which are complexed with various compounds, e.g., HDM2 inhibitors.

Abstract translation: 本发明涉及与各种化合物例如HDM2抑制剂复合的HDM2多肽及其突变体。

公开(公告)号：US06645966B2

公开(公告)日：2003-11-11

申请号：US10053335

申请日：2002-01-18

Applicant: William T. Windsor ,  Patricia C. Weber ,  Corey O. Strickland ,  Michael Gelb

Inventor： William T. Windsor ,  Patricia C. Weber ,  Corey O. Strickland ,  Michael Gelb

IPC: A61K31495

CPC classification number: C07D231/12 ,  A61K31/4178 ,  A61K31/454 ,  A61K31/4545 ,  A61K31/4725 ,  A61K31/496 ,  A61K45/06 ,  C07D233/56 ,  C07D249/08 ,  C07D401/14 ,  C07D403/12 ,  Y02A50/411 ,  Y10S514/895 ,  A61K2300/00

Abstract: Disclosed is a method of treating Malaria comprising administering an effective amount of an FPT inhibitor to a patient in need of such treatment alone or in combination with an additional antimalarial agent and/or agent for reversing antimalarial resistance. Also disclosed are novel Farnesyl Protein Transferase inhibitors.

Abstract translation: 公开了一种治疗疟疾的方法，其包括向需要这种治疗的患者单独施用有效量的FPT抑制剂或与用于逆转抗疟药抗性的另外的抗疟药剂和/或试剂组合施用有效量的FPT抑制剂。还公开了新的法呢基蛋白转移酶抑制剂 。