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1.
J Med Chem ; 64(19): 14603-14619, 2021 10 14.
Article in English | MEDLINE | ID: mdl-34596404

ABSTRACT

Herein, we report the discovery of a novel class of quinazoline carboxamides as dual p70S6k/Akt inhibitors for the treatment of tumors driven by alterations to the PI3K/Akt/mTOR (PAM) pathway. Through the screening of in-house proprietary kinase library, 4-benzylamino-quinazoline-8-carboxylic acid amide 1 stood out, with sub-micromolar p70S6k biochemical activity, as the starting point for a structurally enabled p70S6K/Akt dual inhibitor program that led to the discovery of M2698, a dual p70S6k/Akt inhibitor. M2698 is kinase selective, possesses favorable physical, chemical, and DMPK profiles, is orally available and well tolerated, and displayed tumor control in multiple in vivo studies of PAM pathway-driven tumors.


Subject(s)
Neoplasms , Protein Kinase Inhibitors , Proto-Oncogene Proteins c-akt , Ribosomal Protein S6 Kinases, 70-kDa , Animals , Humans , Cell Line, Tumor , High-Throughput Screening Assays , Neoplasms/drug therapy , Neoplasms/enzymology , Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Signal Transduction/drug effects , Stereoisomerism , Structure-Activity Relationship , TOR Serine-Threonine Kinases/drug effects
2.
Bioorg Med Chem Lett ; 24(9): 2168-72, 2014 May 01.
Article in English | MEDLINE | ID: mdl-24685543

ABSTRACT

Follicle-stimulating hormone (FSH), acting on its receptor (FSHR), plays a pivotal role in the stimulation of follicular development and maturation. Multiple injections of protein formulations are used during clinical protocols for ovulation induction and for in vitro fertilization that are followed by a selection of assisted reproductive technologies. In order to increase patient convenience and compliance several research groups have searched for orally bioavailable FSH mimetics for innovative fertility medicines. We report here the discovery of a series of substituted benzamides as positive allosteric modulators (PAM) targeting FSHR. Optimization of this series has led to enhanced activity in primary rat granulosa cells, as well as remarkable selectivity against the closely related luteinizing hormone receptor (LHR) and thyroid stimulating hormone receptor (TSHR). Two modulators, 9j and 9k, showed promising in vitro and pharmacokinetic profiles.


Subject(s)
Allosteric Regulation/drug effects , Benzamides/chemistry , Benzamides/pharmacology , Follicle Stimulating Hormone/metabolism , Animals , CHO Cells , Cells, Cultured , Cricetulus , Female , Follicle Stimulating Hormone/agonists , Granulosa Cells/drug effects , Granulosa Cells/metabolism , Humans , Rats
3.
J Am Chem Soc ; 128(33): 10943-51, 2006 Aug 23.
Article in English | MEDLINE | ID: mdl-16910691

ABSTRACT

Dynamic resolution has been studied as a method for the asymmetric synthesis of 2-substituted pyrrolidines. Highly enantioselective electrophilic substitutions of racemic 2-lithiopyrrolidines in the presence of a chiral ligand have been achieved. The organolithium compounds were prepared by tin-lithium exchange from the corresponding tributylstannanes and n-butyllithium or by deprotonation of N-(tert-butyloxycarbonyl)pyrrolidine with sec-butyllithium. A range of N-substituents and chiral ligands were investigated for the dynamic resolution. Electrophilic quench of the resolved diastereomeric 2-lithiopyrrolidine-chiral ligand complexes provided the enantiomerically enriched 2-substituted pyrrolidines. With N-alkyl derivatives, the resolution occurs conveniently at (or just below) room temperature and either enantiomer of the product can be formed by appropriate choice of the chiral ligand. The asymmetric induction occurs as a result of a thermodynamic preference for one of the diastereomeric complexes. The minor complex was found to have a faster rate of reaction with the electrophile. The use of N-allylic derivatives provides a means to prepare the N-unsubstituted pyrrolidine products. Best results were obtained with the N-2,3-dimethylbut-2-enyl derivative, and this N-substituent could be cleaved using 1-chloroethyl chloroformate. With N-Boc-2-lithiopyrrolidine, the enantioselectivity arises by a kinetic resolution and high levels of asymmetric induction in the presence of excess n-butyllithium can be obtained. Dynamic kinetic resolution of the N-Boc derivative is limited in the scope of electrophile that can be used.

4.
J Am Chem Soc ; 128(13): 4174-5, 2006 Apr 05.
Article in English | MEDLINE | ID: mdl-16568961

ABSTRACT

An intermediate phosphonium salt has never been isolated from the Morita-Baylis-Hillman (MBH) reaction. Due to the weakly basic counterion produced in the MBH alkylation and allylation reactions, the reaction can be stopped after electrophilic attack on the zwitterionic enolate and an intermediate isolated. Upon analysis of the crystal structure, a trans geometry is observed, suggesting that there is no electrostatic interaction between phosphorus and oxygen in the zwitterionic enolate that undergoes alkylation, thus giving new mechanistic insight into the MBH reaction.

5.
Chem Commun (Camb) ; (46): 5772-4, 2005 Dec 14.
Article in English | MEDLINE | ID: mdl-16307141

ABSTRACT

sp3 Hybridized electrophiles, never before used in the organomediated Morita-Baylis-Hillman reaction, now facilitate the formation of five- and six-membered enone cycloalkylation products.

6.
J Am Chem Soc ; 127(29): 10168-9, 2005 Jul 27.
Article in English | MEDLINE | ID: mdl-16028918

ABSTRACT

We have developed the Morita-Baylis-Hillman reaction to include, for the first time in a completely organomediated process, intramolecular examples bearing allylic leaving groups as the electrophilic partner providing a facile, high yielding, straightforward synthesis of densely functionalized cyclic molecules.

7.
Org Biomol Chem ; 1(9): 1532-44, 2003 May 07.
Article in English | MEDLINE | ID: mdl-12926284

ABSTRACT

The synthesis of chiral 1,2-diamines and 1,3-diamines was achieved from the unsubstituted diamines by way of N-tert-butoxycarbonyl (Boc) substituted imidazolidines (tetrahydroimidazoles) and pyrimidines (hexahydro-1,3-diazines), which were treated with sec-butyllithium to effect deprotonation alpha- to the N-Boc group, followed by addition of an electrophile to give substituted products that could be hydrolysed under acidic conditions to give the substituted 1,2- or 1,3-diamines. Use of the chiral ligand (-)-sparteine promoted asymmetric deprotonation of the imidazolidine substrates to give, after hydrolysis, enantiomerically enriched 1,2-diamines.


Subject(s)
Diamines/chemical synthesis , Imidazoles/chemistry , Pyrimidines/chemistry
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