Synthesis of highly potent and selective hetaryl ureas as integrin alpha(V)beta3-receptor antagonists

Solid-phase synthesis and SAR of integrin alpha(V)beta3-receptor antagonists containing a urea moiety as non-basic guanidine mimetic are described. The most potent compounds exhibited IC(50) values towards alpha(V)beta3 in the nanomolar range and high selectivity versus related integrins like alpha(IIb)beta3. For selected examples efficacy in functional cellular assays is demonstrated.     

Synthesis of pyrazoles and isoxazoles as potent alpha(v)beta3 receptor antagonists

We describe a series of pyrazole and isoxazole analogs as antagonists of the alpha(v)beta3 receptor. Compounds showed low to sub-nanomolar potency against alpha(v)beta3, as well as good selectivity against alpha(IIb)beta3. In HT29 cells, most analogs also demonstrated significant selectivity against alpha(v)beta6. Several compounds showed good pharmacokinetic properties in rats, in addition to anti-angiogenic activity in a mouse corneal micropocket model. Compounds were synthesized in a straightforward manner from readily available glutarate precursors.     

Synthesis and SAR study of novel pseudo-steroids as potent and selective progesterone receptor antagonists

Synthesis of novel 7-pseudo-steroids 1c has been achieved from trenbolone 3 via an efficient 14 step sequence with overall yields of 10–15%. Various substitutions were incorporated at both the aromatic side chain as well as the D ring. The orientation of aromatic side chain at C10 plays a crucial role for progesterone receptor (PR) activity. Compound 2a (T47D = 1 nM) with –NMe₂ para to the aromatic group along with spirofurane groups in the D ring was the optimal substitution. All compounds were also evaluated for glucocorticoid receptor (GR) antagonist activities in vivo in a rat and found efficacious in uterine complement C3 assay via the oral route of administrations.     

Synthesis of cinnamic acids and related isosteres as potent and selective alpha v beta 3 receptor antagonists

We describe a series of conformationally-restricted cinnamic acid peptidomimetics as well as several cinnamic acid isosteres, including 3-phenylpropionic acids, 2-amino-3-phenylpropionic acids, phenoxyacetic acids and 2-phenylcyclopropylcarboxylic acids. Several analogues demonstrated low to sub-nanomolar potencies against alpha(v)beta(3) and greater than 200-fold selectivity against the other beta(3) integrin alpha(IIb)beta(3). In whole 293 cells, many of these analogues also showed modest selectivity against other alpha(v) integrins such as alpha(v)beta(1) and alpha(v)beta(5). These compounds were synthesized from readily available starting materials using either Heck or Mitsunobu coupling conditions.     

Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part 2: synthesis of potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists

We synthesized 4-aminopiperidine derivatives of our prototype integrin alpha(v)beta3 antagonist 1 in an attempt to increase the activity and water solubility. Introduction of one or two hydrophilic moieties into the central aromatic ring and/or the benzene ring at the C-terminus of 1 increased water solubility and enhanced inhibition of cell adhesion. The results of a structure-activity relationships (SAR) study indicated that the torsion angle between the central aromatic ring and the piperidine ring, and the acidity at the sulfonamide moiety, might be important for alpha(v)beta3 receptor binding activity. Some of these compounds are novel and potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists with acceptable water solubility and a satisfactory early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile.     

Camphor sulfonamide derivatives as novel,potent and selective CXCR3 antagonists

A series of N-arylpiperazine camphor sulfonamides was discovered as novel CXCR3 antagonists. The synthesis, structure–activity relationships, and optimization of the initial hit that resulted in the identification of potent and selective CXCR3 antagonists are described.     

Synthesis and SAR of highly potent and selective dopamine D(3)-receptor antagonists: 1H-pyrimidin-2-one derivatives

The synthesis and SAR of novel highly potent and selective dopamine D(3)-receptor antagonists based on a 1H-pyrimidin-2-one scaffold are described. A-690344 antagonized PD 128907-induced huddling deficits in rat (ED(50) 6.1mg/kg po), a social interaction paradigm.     

Synthesis and SAR of potent and selective androgen receptor antagonists: 5,6-Dichloro-benzimidazole derivatives

The synthesis and in vivo SAR of 5,6-dichloro-benzimidazole derivatives as novel selective androgen receptor antagonists are described. During screening of 2-alkyl benzimidazoles, it was found that a trifluoromethyl group greatly enhances antagonist activity in the prostate. Benzimidazole 1 is a potent AR antagonist in the rat prostate (ID50 = 0.15 mg/day).     

Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part III: synthesis of potent antagonists with alpha(v)beta3/alpha(IIb)beta3 dual activity and improved water solubility

In order to optimize our novel integrin alpha(v)beta3/alpha(IIb)beta3 dual antagonists, spatial screening at the N-terminus was performed. The alpha(v)beta3 antagonistic activity varied depending on the space that was occupied by the N-terminus, but high potency against alpha(IIb)beta3 was well maintained. The (3S)-aminopiperidine analogue had the strongest activity against alpha(v)beta3, and the S isomer at piperidine was more potent than the R isomer. Compounds selected on the basis of SAR analysis of a novel lead compound showed acceptable early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and sufficient water solubility for use as infusion drugs. Docking studies with the alpha(v)beta3 receptor were performed to confirm the SAR findings.     

Synthesis of 2,5-thiazole butanoic acids as potent and selective alpha(v)beta3 integrin receptor antagonists with improved oral pharmacokinetic properties

We describe a series of 2,5 thiazole containing compounds, which are potent antagonists of the integrin alpha(v)beta3 and show selectivity relative to the other integrins, such as alpha(IIb)beta3 and alpha(v)beta6. These analogs were demonstrated to have high bioavailability relative to other relative heterocyclic analogs.     

Identification of 3-sulfonylindazole derivatives as potent and selective 5-HT(6) antagonists

As part of our efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT₆ receptor in order to identify potent and selective ligands for this purpose. Herein we report the identification of a novel series of 3-sulfonylindazole derivatives with acyclic amino side chains as potent and selective 5-HT₆ antagonists. The synthesis and detailed SAR of this class of compounds are reported.     

Substituted benzocyloheptenes as potent and selective alpha(v) integrin antagonists

A novel series of potent and specific alpha(v) integrin antagonists has been obtained by aminoalkyl substitutions on benzocyloheptene acetic acids as a rigid GD bioisostere. The preferred compounds 1-2, 1-3 and 1-8, showed nano- to subnanomolar IC(50) values on alpha(v)beta(3) and alpha(v)beta(5) integrins, with favorable pharmacokinetics.     

Discovery of novel oxazolidinedione derivatives as potent and selective mineralocorticoid receptor antagonists

Novel oxazolidinedione analogs were discovered as potent and selective mineralocorticoid receptor (MR) antagonists. Structure–activity relationship (SAR) studies were focused on improving the potency and microsomal stability. Selected compounds demonstrated excellent MR activity, reasonable nuclear hormone receptor selectivity, and acceptable rat pharmacokinetics.     

Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent alpha(4)beta(1) integrin antagonists

A series of isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives derived from LDV was found to be a potent antagonist of the alpha(4)beta(1) integrin. The synthesis and SAR leading up to 3-[3-(1-[-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino]-3-methyl-butyl)-isoxazol-5-yl]-propionic acid (22) are reported. In an allergic mouse model, compound 22 was efficacious delivered systemically (58% inhib @ 10 mg/kg, sc) as well as by intra-tracheal instillation (ED(50)=2 microg/kg).     

N-(3-phenylsulfonyl-3-piperidinoyl)-phenylalanine derivatives as potent,selective VLA-4 antagonists

The SAR of 1-sulfonyl-cyclopentyl carboxylic acid amides, ligands for the VLA-4 integrin, was investigated. This effort resulted in the identification of N-(3-phenylsulfonyl-3-piperidinoyl)-(L)-4-(2',6'-dimethoxyphenyl)phenylalanine 52 as a potent, selective VLA-4 antagonist (IC(50)=90 pM). Expansion of the SAR demonstrated that this structural unit can be used to identify a diverse series of sub-nanomolar antagonists.     

Discovery of novel phenylpyridone derivatives as potent and selective MCH1R antagonists

The design, synthesis and structure-activity relationships of a novel class of N-phenylpyridone MCH1R antagonists are described. The core part of the N-phenylpyridone structure was newly designed and the side chain moieties that were attached to the core part were extensively explored. As a result of optimization of the N-phenylpyridone leads, we successfully developed the orally available, and brain-penetrable MCH1R selective antagonist 7c, exhibiting excellent anti-obese effect in diet-induced obese (DIO) mice.     

Discovery and evaluation of piperidinyl carboxylic acid derivatives as potent alpha(4)beta(1) integrin antagonists.

Piperidinyl carboxylic acid-based derivatives were prepared as antagonists of the leukocyte cell adhesion process that is mediated through the interaction of the alpha(4)beta(1) integrin (VLA-4, very late antigen 4) and the vascular cell adhesion molecule 1 (VCAM-1). Compounds 2a-h inhibited the adhesion in a cell-based assay in the low and sub micromolar range, a pharmacokinetic study of 2d is reported.     

N-Methylbenzanilide derivatives as a novel class of selective V(1A) receptor antagonists.

During our efforts to develop a novel class of selective V(1A) receptor antagonists, the N-methylbenzanilide structure was applied to a 4,4-difluoro-1-benzazepine derivative, 4, which is a selective V(1A) receptor antagonist. Further structural modifications gave 16a with high V(1A) affinity and V(2)/V(1A) selectivity (K(i)=5.71 nM, V(2)/V(1A)=140) and potent V(1A) receptor antagonist activity (ID(50)=0.0080 mg/kg iv).     

Parallel synthesis and SAR study of novel oxa-steroids as potent and selective progesterone receptor antagonists

Efficient parallel synthesis of novel 7-oxa-steroids 4 has been achieved from the key intermediate 3 via a one-pot four-step sequence. oxa-Steroids 4 with various ortho-, meta-, and para-monosubstituents on the phenyl ring, as well as disubstituted phenyl and heterocycles, were evaluated for progesterone receptor (PR) and glucocorticoid receptor (GR) antagonist activities. SAR study demonstrated that the para-fluorinated substituents on the phenyl ring not only increased the potency for PR in a T47D cell functional assay, but also improved the selectivity over GR in an A549 cell functional assay. The para-fluorophenyl oxa-steroid 4l and the para-trifluoromethylphenyl oxa-steroid 4p were found to be remarkably more potent and more selective PR antagonists than mifepristone, with subnanomolar potency and about 140-fold selectivity over GR. Molecular modeling of the oxa-steroid bound to PR provided meaningful insight for the SAR study. oxa-Steroids 4a and 4b were found to be more efficacious than mifepristone in vivo in a rat uterine complement C3 assay via the oral route, although they were less than or equally potent to mifepristone in the T47D assay.     

Synthesis and SAR of novel imidazoles as potent and selective cannabinoid CB2 receptor antagonists with high binding efficiencies

The synthesis and structure–activity relationship studies of imidazoles are described. The target compounds 6–20 represent a novel chemotype of potent and CB₂/CB₁ selective cannabinoid CB₂ receptor antagonists/inverse agonists with very high binding efficiencies in combination with favourable log P and calculated polar surface area values. Compound 12 exhibited the highest CB₂ receptor affinity (K_i = 1.03 nM) in this series, as well as the highest CB₂/CB₁ subtype selectivity (>9708-fold).