From atoms to bits: Resource mobilization of non-digital, hybrid, and digital cleantech startups.

Climate change is one of the most critical challenges to tackle in this century, where innovations developed and commercialized by cleantech startups are crucial contributors to achieve emission reduction targets. Entrepreneurship scholars have long presumed that resource mobilization is essential for startups to transit successfully through the conception and commercialization life cycle stages. Yet, we have a limited understanding of how resource mobilization varies across the three startups types of non-digital, hybrid - an intermediate type of non-digital and digital startups -, and digital cleantech startups.

Lead Optimization to Advance Protease-Activated Receptor-1 Antagonists in Early Discovery.

Vorapaxar is an approved drug for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Subsequent to the discovery of Vorapaxar, medicinal chemistry efforts were continued to identify structurally differentiated leads. Toward this goal, extensive structure-activity relationship studies using a C-ring-truncated version of Vorapaxar culminated in the discovery of three leads, represented as , , and .

Inhibition of Factor XIa Reduces the Frequency of Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits.

Factor XI (FXI) is an integral component of the intrinsic pathway of the coagulation cascade and plays a critical role in thrombus formation. Because its role in the pathogenesis of cerebral microembolic signals (MES) is unclear, this study used a potent and selective small molecule inhibitor of FXIa, compound 1, to assess the effect of FXI blockade in our recently established preclinical model of cerebral MES induced by FeCl injury of the carotid artery in male New Zealand White rabbits. Ascending doses of compound 1 were evaluated simultaneously for both carotid arterial thrombosis by a Doppler flowmeter and MES in the middle cerebral artery by a transcranial Doppler.

A new biarticular actuator design facilitates control of leg function in BioBiped3.

Bioinspired legged locomotion comprises different aspects, such as (i) benefiting from reduced complexity control approaches as observed in humans/animals, (ii) combining embodiment with the controllers and (iii) reflecting neural control mechanisms. One of the most important lessons learned from nature is the significant role of compliance in simplifying control, enhancing energy efficiency and robustness against perturbations for legged locomotion. In this research, we investigate how body morphology in combination with actuator design may facilitate motor control of leg function.

A rabbit model of cerebral microembolic signals for translational research: preclinical validation for aspirin and clopidogrel.

Unlabelled: Essentials Microembolic signal (MES) is an independent predictor of stroke risk in patients. A rabbit model of cerebral microembolic signals was established. Therapeutic efficacy was demonstrated for aspirin and clopidogrel on microembolic signals.

Himbacine-derived thrombin receptor antagonists: c7-spirocyclic analogues of vorapaxar.

We have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (K i = 5.

Himbacine-derived thrombin receptor antagonists: c7-aminomethyl and c9a-hydroxy analogues of vorapaxar.

We have synthesized several C7-aminomethyl analogues of vorapaxar that are potent PAR-1 antagonists. Many of these analogues showed excellent in vitro binding affinity and pharmacokinetics profile in rats. Compound 6a from this series showed excellent PAR-1 activity (K i = 5 nM).

Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia.

Structure-guided optimization of a series of C-5 alkyl substituents led to the discovery of a potent nicotinic acid receptor agonist SCH 900271 (33) with an EC50 of 2 nM in the hu-GPR109a assay. Compound 33 demonstrated good oral bioavailability in all species. Compound 33 exhibited dose-dependent inhibition of plasma free fatty acid (FFA) with 50% FFA reduction at 1.

Discovery of a potent nicotinic Acid receptor agonist for the treatment of dyslipidemia.

Nicotinic acid has been used clinically for decades to control serum lipoproteins. Nicotinic acid lowers very low-density lipoprotein (VLDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, and lipoprotein-a (LPa), and it is also effective in raising high-density lipoprotein (HDL)-cholesterol. However, nicotinic acid has several side effects in clinical use.

Discovery of a vorapaxar analog with increased aqueous solubility.

An analog of the thrombin receptor antagonist vorapaxar (SCH 530348) with increased aqueous solubility, compound 9c (SCH 602539), was discovered through incorporation of polar substituents on the pyridine ring of the himbacine-derived lead series. This analog retained the excellent potency, pharmacokinetic and safety properties of vorapaxar while increasing the aqueous solubility by 20-fold. Also presented are in vivo evaluations of this compound in a cynomolgus monkey platelet aggregation assay and in a Folts model of thrombosis in anesthetized monkeys.

SCH 602539, a protease-activated receptor-1 antagonist, inhibits thrombosis alone and in combination with cangrelor in a Folts model of arterial thrombosis in cynomolgus monkeys.

Objective: To determine the antithrombotic effects of SCH 602539, an analog of the selective protease-activated receptor (PAR)-1 antagonist vorapaxar (formerly SCH 530348) currently in advanced clinical development, and the P2Y(12) ADP receptor antagonist cangrelor, alone and in combination.

Methods And Results: Multiple platelet activation pathways contribute to thrombosis. The effects of SCH 602539 and cangrelor alone and in combination on cyclic flow reductions were evaluated in a Folts model of thrombosis in cynomolgus monkeys.

Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity.

The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients.

Optimization of purine based PDE1/PDE5 inhibitors to a potent and selective PDE5 inhibitor for the treatment of male ED.

In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.

SAR development of polycyclic guanine derivatives targeted to the discovery of a selective PDE5 inhibitor for treatment of erectile dysfunction.

Development of structure-activity relationship of cyclic guanines I lead us to discovery of a potent and selective series of phosphodiesterase 5 inhibitors 52-59 (IC50=1.3-11.0 nM, PDE6/5=116-600).

Design and synthesis of xanthine analogues as potent and selective PDE5 inhibitors.

We have discovered potent and selective xanthine PDE5 inhibitors. Compound 25 (PDE5 IC(50)=0.6 nM, PDE6/PDE5=101) demonstrated similar functional efficacy and PK profile to Sildenafil (PDE5 IC(50)=3.

Activation of central melanocortin receptors by MT-II increases cavernosal pressure in rabbits by the neuronal release of NO.

1. Melanotan-II had been reported to cause penile erections in men with erectile dysfunction. In the present study, we investigated the mechanisms by which systemic administration of MT-II increases intracavernosal pressure in anaesthetized rabbits.

Phentolamine mesylate relaxes rabbit corpus cavernosum by a nonadrenergic, noncholinergic mechanism.

The contribution of NO-cGMP dependent pathway to phentolamine mesylate-evoked nonadrenergic, noncholinergic relaxation of rabbit corpus cavernosum was investigated in vitro. Stimulation of nonadrenergic, noncholinergic neurons of the rabbit corpus cavernosum elicited frequency-related relaxation that was significantly attenuated by L-NAME (NO synthase inhibitor) or ODQ (an inhibitor of guanylate cyclase). Moreover, tetrodotoxin, a sodium channel blocker, abolished the electrical field stimulation-induced relaxation of rabbit corpus cavernosum, suggesting that neuronal release of NO mediates relaxation to electrical field stimulation.

Sildenafil relaxes rabbit clitoral corpus cavernosum.

The role of phosphodiesterase type 5 inhibition in the modulation of female sexual dysfunction was investigated by assessing its effects on in vitro relaxation of rabbit clitoris. Stimulation of the non-adrenergic, non-cholinergic neurons of the clitorus elicited a frequency-dependent relaxation response. Inhibition of NO synthase with L-NAME (100 microM) or inhibition of soluble guanylate cyclase with ODQ (1.

Inhibition of platelet adhesion and aggregation by E4021, a type V phosphodiesterase inhibitor, in guinea pigs.

E4021 (sodium 1-[6-chloro-4-(3, 4-methylenedioxybenzyl)-aminoquinazolin-2-yl]piperidine-4-ca rboxylate sesquihydrate) is a highly selective and potent inhibitor of type V phosphodiesterase(PDE5). The in vitro and in vivo effect of E4021 on platelet function was evaluated, using echistatin, a potent disintegrin, as a positive reference agent. E4021 inhibits aggregatory response to collagen in washed human platelets (IC50 = 5 microM, vs.

In vivo inhibition of platelet adhesion by a cGMP-mediated mechanism in balloon catheter injured rat carotid artery.

The role of cyclic guanosine monophosphate (cGMP) versus cyclic adenosine monophosphate (cAMP) mediated mechanism in modulating platelet adhesion was investigated in balloon catheter injured rat carotid arteries. Vascular injury with balloon angioplasty significantly increased the adherence of platelets to the injured carotid arteries. Intravenous infusion of zaprinast (1 mg/kg/min), a cGMP phosphodiesterase inhibitor, or sodium nitroprusside (8 micrograms/kg/min), a stimulator of soluble guanylate cyclase, significantly attenuated the adherence of platelets to the injured carotid arteries.

Phosphoramidon does not inhibit endogenous endothelin-1 release stimulated by hemorrhage, cytokines and hypoxia in rats.

The role of phosphoramidon-sensitive endothelin converting enzyme in the release of endogenous endothelin-1 was investigated in anesthetized rats. Intravenous infusion of phosphoramidon 0.3 mg/kg/min did not suppress the release of endothelin-1 stimulated by hemorrhage or cytokines.

A method for maintaining and protecting chronic arterial and venous catheters in conscious rats.

The ability to monitor arterial blood pressure and heart rate directly, as well as to sample venous blood, or inject pharmaceutical agents intravenously is important in pharmacological studies of the cardiovascular system. The rat is a frequently used and accepted animal model for cardiovascular investigations, especially those relating to hypertension. Even though the rat is a major model for these studies, the size of the rat has made it difficult to maintain catheters for a long period of time.